Crystalline n-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-n- methyl-2-[4-(2-pyridinyl)phenyl]acetamide mono mesylate  monohydrate having a specific particle size distribution  range and a specific surface area range for use in  pharmaceutical formulations

ABSTRACT

The present invention relates to the crystalline mono mesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide in a definite particle size range, particle size distribution and a specific surface area range, which has demonstrated increased long term stability and release kinetics from pharmaceutical compositions, as well as to pharmaceutical compositions containing said crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mono mesylate monohydrate having the afore-mentioned particle size range, particle size distribution and specific surface area range. Moreover, the present invention relates to the pharmacokinetic and pharmacodynamic in vivo profiles of the resultant free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide after administration of the afore-mentioned crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide mono mesylate monohydrate salt to a subject in need thereof.

The present invention relates to the crystalline mono mesylatemonohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1, 3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl] -acetamide in adefinite particle size range, particle size distribution and a specificsurface area range, which has demonstrated increased long term stabilityand release kinetics from pharmaceutical compositions, as well as topharmaceutical compositions containing said crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mono mesylatemonohydrate salt having the afore-mentioned particle size range,particle size distribution and specific surface area range.

Furthermore, the present invention relates to the pharmacokinetic (PK)and pharmacodynamic (PD) in vivo profiles of the free base form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide resultingfrom crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide monomesylate monohydrate salt administration to a subject in need thereof,whereby said mono mesylate monohydrate salt is administered in apharmaceutical composition of the invention.

The resulting PK/PD profiles of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide are usefulin methods of treating and/or prophylaxis of herpesviruses andinfections caused by herpesviruses and/or preventing from transmissionof a herpes virus or herpesviruses in accordance with the invention.

BACKGROUND OF THE INVENTION

Synthesis of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is known fromEP 1244641 B1, and the use of acidic components includingmethanesulfonic acid for the formulation of tablets containingmicronized N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide is disclosedby WO 2006/103011 A1.

It is the objective of the present invention to provide a specific formof a salt of the compound N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide whichexhibits improved properties in regard to stability and bioavailability,and thus makes this specific form of the salt preferable for themanufacturing of pharmaceutical compositions and to providepharmaceutical compositions containing such a specific salt so thatthese pharmaceutical compositions exhibit improved properties in regardto stability and bioavailability of the contained specific form of asalt of the compound N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide. Hereby, itshould be noted that in accordance with the invention only the free baseform ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamideexhibits bioavailability in a subject since the administered crystallinemono mesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide turns invivo into the corresponding free base form.

Accordingly, another aspect of the present invention is directed to thePK profiles resulting from administration of the crystalline monomesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide in vivo,when administered in a pharmaceutical composition of the instantinvention to a subject in need thereof. The PK in vivo profiles of thefree base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide enablesufficient absolute bioavailability of 70%±30% thereof.

The objectives of the present invention are solved by the teaching ofthe independent claims. Further advantageous features, aspects, anddetails of the invention are evident from the dependent claims, thedescription, the drawings (Figs.), and the examples of the presentapplication.

DESCRIPTION OF THE INVENTION

At room temperature, there are four polymorphic forms and an amorphousform of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide.In addition, several solvates can be detected for the free base ofN-[5-(aminosulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide dependingon the solvent. Based on the existence of the afore-mentioned forms ofthe free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamideat room temperature, no conclusion on thermic stability can be drawn.Hence, the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamideis not suitable for a long-term stable formulation, because long-termproperties of the free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide cannot bedetermined. In addition, the low solubility is responsible forunfavorable drug release and resorption properties compared to thecrystalline mono mesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide.

Surprisingly, it was found that the crystalline mono mesylatemonohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide overcomesall drawbacks of the free base or other salts, if said crystalline monomesylate monohydrate salt has a specific PSD (particle sizedistribution), PSR (particle size range) and SSA (specific surfacearea). This also results in advantageous PK/PD in vivo profiles of theresultant free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide as thepharmacologic active component resulting from administration of thecrystalline mono mesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acet-amide. Thus, thepresent invention relates to the crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate of the following formula

wherein the crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate particles have a particle sizerange from 1 to 500 μm, a particle size distribution which is defined byd(0.1) from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9) from 70 to400 μm and a specific surface area of less than 1.0 m²/g.

The synthesis of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate is shown below

The above synthesis uses a boronic acid derivative, a borolane or aborinane reagent which is reacted with ethyl-4-bromophenylacetate inorder to obtain the key intermediate (4-pyridin-2-ylphenyl) acetic acidin a single stage with an overall yield of about 40% of theory. The(4-pyridin-2-ylphenyl)acetic acid is reacted with4-methyl-2-(methylamino)-1, 3-thiazole-5-sulfonamide to the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, which isthen converted to the definite crystalline mono mesylate monohydratesalt exhibiting a specific PSD, PSR and SSA. The single reaction stepsfor the synthesis of the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomesylate monohydrate salt are summarized below.

Step A: Reacting compound A of the following general formula A*

wherein R¹ represents a leaving group and R² represents an alkyl residuewith 1 to 6 carbon atoms or a cycloalkyl residue with 3 to 6 carbonatoms, with a boronic acid derivative, borolane, borinane or diboronicacid reagent under elimination of R¹-H or R¹-B(OR)₂ and formation of anintermediate boronic acid derivative of compound A, wherein preferredcatalysts for the reaction are the reagent systems palladium acetatewith triethylamine and with triphenylphosphine or PdCl₂(PPh₃)₂ withtriethylamine, wherein the intermediate boronic acid derivative is thenreacted with the pyridine compound B of the following general formula B*

wherein R³ represents a leaving group under basic conditions in order toobtain the (4-pyridin-2-ylphenyl)acetic acid as an alkaline solution ofthe corresponding carboxylate salt.

The resulting (4-pyridin-2-ylphenyl)acetic acid was purified by simplewashing steps at different pH and filtration steps followed byprecipitation or crystallization, preferably by properly adjusting thepH of an aqueous acidic solution of (4-pyridin-2-ylphenyl)acetic acidwith an appropriate amount of base to 3.5-5.0, preferably 3.8-4.7.Beside the simple washing and filtration steps, no further purificationof the (4-pyridin-2-ylphenyl)acetic acid or any of the intermediates, asfor instance by recrystallization or chromatography, is required.

Step B: Reacting (4-pyridin-2-ylphenyl)acetic acid obtained from step Awith 4-methyl-2-(methylamino)-1, 3-thiazole-5-sulfonamide

in order to obtainN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamideof the formula

The free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide isthereafter most preferably converted (as step C) to the so far unknownmonohydrate of the mono mesylate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide. TheobtainedN-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidemono mesylate monohydrate is then formulated as particles having aparticle size in the range from 1 μm to 500 μm and a particle sizedistribution defined by d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210μm and d(0.9) from 70 to 400 μm and a specific surface area of theparticles less than 1.0 m²/g, and more preferably a PSD defined byd(0.1) from 10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to350 μm with a SSA of the particles less than 0.3 m²/g.

In the above synthesis, the term “leaving group” as used herein is amolecular fragment that departs with a pair of electrons in heterolyticbond cleavage. Leaving groups can be anions or neutral molecules. Commonanionic leaving groups are halides such as Cl⁻, Br⁻, and I⁻, andsulfonate esters, such as para-toluenesulfonate (“tosylate”, TsO⁻),trifluoromethanesulfonate (“triflate”, TfO⁻, CF₃SO₂O⁻), benzenesulfonate(“besylate,” C₆H₅SO₂O⁻) or methanesulfonate (“mesylate”, MsO⁻).

General formula A* as shown below

covers all phenyl acetic acid esters having a leaving group on thephenyl residue in position 4.

Thus R¹ preferably represents —F, —Cl, —Br, —I, —OMs, —OTf and —OTs. Thegroup “—OMs” refers to —OMesylate, the group “—OTf” refers to —OTriflateand the group “—OTs” refers to —OTosylate.

The group R² represents an alkyl residue with 1 to 6 carbon atoms or acycloalkyl residue with 3 to 6 carbon atoms, and preferably —CH₃, —C₂H₅,—C₃H₇, —CH(CH₃)₂, —C₄H₉, —CH₂-CH(CH₃)₂, —CH(CH₃)—C₂H₅, —C(CH₃)₃, —C₅H₁₁,—C₆H₁₃, cyclo-C₃H₅, cyclo-C₄H₇, cyclo-C₅H₉, cyclo-C₆H₁₁. More preferredare —CH₃, —C₂H₅, —C₃H₇, —CH(CH₃)₂, —C₄H₉, —CH₂—CH(CH₃)₂, —CH(CH₃)—C₂H₅,—C(CH₃)₃, and —C₅H₁₁. Especially preferred are —CH₃, —C₂H₅, —C₃H₇, and—CH(CH₃)₂.

Various boronic acid derivatives, borolanes and borinanes as well as thecorresponding diboronic acid derivatives can be used in step A of theinventive synthesis disclosed herein. Preferred are borolanes of thefollowing general formula:

wherein R′ and R″ are independently of each other any substituted orunsubstituted, linear or branched alkyl group with 1 to 10 carbon atomsor cycloalkyl group with 3 to 10 carbon atoms, or R′ and R″ can alsoform together with the boron atom a heterocyclic ring wherein R′ and R″together form a substituted or unsubstituted, linear or branched alkenegroup with 2 to 10 carbon atoms. Preferably R′ and R″ representindependently of each other —CH₃, —C₂H₅, —C₃H₇, —CH(CH₃)₂, —C₄H₉,—CH₂—CH(CH₃)₂, —CH(CH₃)-C₂H₅, —C(CH₃)₃, and —C₅H₁₁. The cyclic borolanesare preferred.

The following borolanes, borinanes and diboronic acid derivatives arepreferred:

wherein R^(a), R^(b), R^(c), R^(d), R^(e) and R^(f) representindependently of each other a substituted or unsubstituted, linear orbranched alkyl group with 1 to 10 carbon atoms or cycloalkyl group with3 to 10 carbon atoms. Preferred are the linear alkyl residues with 1 to6 carbon atoms, and most preferred are —CH₃, —C₂H₅, —C₃H₇ and —CH(CH₃)₂.

Especially preferred examples for the above borone containing compoundsare 4,4,5,5-tetramethyl[1,3,2]dioxaborolane (pinacolborane),[1,3,2]dioxaborolane, [1,3,2]dioxaborinane,5,5-dimethyl[1,3,2]dioxaborinane, 4,6,6-trimethyl[1,3,2]-dioxaborinane,4,4,6,6-tetramethyl[1,3,2]-dioxaborinane,4,4,5,5,6,6-hexamethyl[1,3,2]-dioxaborinane, diisopropoxyborane,hexahydrobenzo[1,3,2]di-oxaborole, 9,9-dimethyl-3,5-dioxa-4-bora-tricyclo-[6.1.1.6^(2,6)]decane,6,9,9-trimethyl-3,5-dioxa-4-bora-tricyclo [6.1.1.6^(2,6)]decane,B2Pin2(bis(pinacolato)diborane), bis(nepentyl glycolato)diboron andcatecholboran.

In step A this boronic acid derivative, borolane, borinane or diboronicacid reagent is reacted with a compound A of general formula A* in orderto obtain an intermediate borolan or borinane reagent which is notisolated and purified. This reaction may be supported by the use ofeither catalysts prepared in situ by combination of palladium salts suchas [Pd(OAc)₂] and PdCl₂ with triphenylphosphine (PPh₃),tri-ortho-tolylphosphine (P(o-To1)₃), tricyclohexylphosphine (PCy₃),tri-tert.-butylphosphine, 1,4-Bis-(diphenylphosphino)-butane (dppb), and1,1′-Bis-(diphenylphosphino)-ferrocene dppf or preformed catalysts suchas Pd(PPh₃)₂Cl₂, Pd(PPh₃)₄, Fibrecat 1032, and Pd(dppf)Cl₂ in thepresence of a variety of organic and inorganic bases such astriethylamine (Et₃N), NaOAc, KOAc, and K₃PO₄. For this reaction heatingto temperature between 70° C. and 150° C., preferably between 80° C. and130° C., more preferably between 90° C. and 110° C. is used. Moreoveraprotic and preferably apolar solvents and preferably aromatic solventssuch as benzene or toluene or xylenes are used.

The intermediate boronic acid reagent is subsequently reacted with apyridinyl compound of the general formula B*, wherein R³ represents aleaving group. Thus, R³ represents —F, —Cl, −Br, −I, —OMs, —OTf and —OTsand preferably —Cl or —Br.

The corresponding (4-pyridin-2-ylphenyl)acetic acid ester is in situtreated with a aqueous base in order to cleave the ester linkage. Itcould be advantageous to heat the reaction mixture during thecoupling/saponification step to moderate temperature and preferably totemperature between 40° C. and 90° C., more preferably between 45° C.and 80° C., still more preferably between 50° C. and 70° C. and mostpreferably between 55° C. and 65° C.

After purification and isolation of the key intermediate(4-pyridin-2-ylphenyl)acetic acid, the (4-pyridin-2-ylphenyl)acetic acidwas obtained in a yield of about 40% of theory including only oneisolation and purification step.

Thereafter the (4-pyridin-2-ylphenyl)acetic acid was reacted with4-methyl-2-(methylamino)-1,3-thiazole-5-sulfonamide of the formula

which was prepared according to the synthesis disclosed in EP 1244641 B1in order to obtain N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide of theformula

ThisN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidewas thereafter converted to the crystalline mono mesylate monohydratesalt, wherein the typical particle size range is from 1 to 500 μm andthe particle size distribution is preferably defined by d(0.1) from 2 to100 μm, d(0.5) from 30 to 210 μm and d(0.9) from 70 to 400 μm andwherein the crystalline particles have a specific surface area of lessthan 1.0 m²/g, and more preferably the PSD is defined by d(0.1) from 10to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to 350 μm and theSSA of the particles is less than 0.3 m²/g.

The parameter d(0.1) refers to the mesh size of a single notional sieveallowing 10% of the total of all particles of the sample to pass. Thusd(0.1)=2-100 μm means that the upper limit of the particle size rangedefining the 10% of smallest particles in the sample is between 2 μm to100 μm. Thus 10% of the total particles have a particle size of not morethan d(0.1) meaning in this case that they have a maximum size of 2 μmto 100 μm.

Accordingly, the parameter d(0.5) refers to the mesh size of a singlenotional sieve allowing 50% of the total of all particles of the sampleto pass. Thus d(0.5)=30-210 μm means that the upper limit of theparticle size range defining the notional half of the sample containingthe smaller particles is between 30 μm to 210 μm. Thus, 50% of the totalof all particles have a particle size of not more than d(0.5) meaning inthis case that they have a maximum size of 30 μm to 210 μm. Accordingly,the parameter d(0.9) refers to the mesh size of a single notional sieveallowing 90% of the total of all particles of the sample to pass i.e.only 10% of the sample is retained. Thus, d(0.9)=70-400 μm means thatthe lower limit of the particle size range defining the 10% of largestparticles in the sample is between 70 μm to 400 μm. Thus 90% of allparticles have a particle size of not more than d(0.9) meaning in thiscase that they have a maximum size of 70 μm to 400 μm.

It is furthermore preferred that the particle size of the crystallineN-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide mesylatemonohydrate particles is within the range of 1 μm to 500 μm, preferablyin the range of 1.5 μm to 450 μm and more preferably in the range of 2μm to 400 μm. Thus, the particle size range (PSR) of the mesylatemonohydrate is from 1.0 μm to 500 μm, preferably from 1.5 μm to 450 μm,more preferably from 2.0 μm to 400 μm, still more preferably from 2.5 μmto 300 μm and most preferably from 3.0 μm to 250 μm. If the PSR is notmentioned at all or if reference to the PSR is made without stating adefinite value, it shall be referred to a particle size range from 1 to500 μm.

Moreover, it is preferred that the particle size distribution of thecrystalline N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acet-amide monomesylate monohydrate particles is characterized by d(0.1) from 4 to 100μm, d(0.5) from 30 to 210 μm and d(0.9) from 70 to 400 μm, morepreferably d(0.1) from 6 to 95 μm, d(0.5) from 50 to 200 μm and d(0.9)from 100 to 390 μm, still more preferably d(0.1) from 7 to 90 μm, d(0.5)from 70 to 190 μm and d(0.9) from 130 to 380 μm, still more preferablyd(0.1) from 8 to 85 μm, d(0.5) from 80 to 185 μm and d(0.9) from 160 to370 μm, still more preferably d(0.1) from 9 to 80 μm, d(0.5) from 90 to180 μm and d(0.9) from 180 to 360 μm, still more preferably d(0.1) from10 to 75 μm, d(0.5) from 100 to 175 μm and d(0.9) from 200 to 350 μm andmost preferably d(0.1) from 11 to 70 μm, d(0.5) from 110 to 170 μm andd(0.9) from 220 to 340 μm.

Furthermore, it is preferred that the specific surface area of thecrystalline particles is less than 1.0 m²/g, more preferably less than0.9 m²/g, still more preferably less than 0.8 m²/g, still morepreferably less than 0.7 m²/g, still more preferably less than 0.6 m²/g,still more preferably less than 0.5 m²/g, still more preferably lessthan 0.4 m²/g and most preferably the SSA of the particles is less than0.3 m2/g.

In a certain aspect of the present invention said specific surface areais typically greater than about 0.01 to 0.06 m²/g, the lower limit notbeing particularly important.

Accordingly, in another aspect of the invention the specific surfacearea is within a range of 0.01 to 0.99 m²/g, preferably within a rangeof 0.05 to 0.99 m²/g, even more preferably within a range of 0.06 to0.99 m²/g, most preferred within a range of 0.06 to 0.29 m²/g.

As used herein the terms “mono mesylate monohydrate”, or “crystallinemono mesylate monohydrate”, or “mono methanesulfonic acid monohydrate”,or “crystalline mono methanesulfonic acid monohydrate”, or “crystallineN-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomesylate monohydrate”, or “N-[5-(amino- sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate” refers to the crystallineN-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamidemono methanesulfonic acid monohydrate having the PSD, PSR and SSA asdefined herein. Thus, these terms ever denote the specific mono mesylatemonohydrate salt in accordance with the invention, whereas the term“free base of N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide”, “freebase form”, and “free base” ever denote the free base form ofN-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide,which also is ever the pharmacologically active form ofN-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide in thehuman body.

With the context of the present invention and the free base ofN-[5-(amino-sulfonyl)-4-methyl-1, 3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide,“pharmacologically active” means acting antiviral in methods of treatingand/or prophylaxis of herpesviruses and infections caused byherpesviruses and/or preventing from transmission of a herpes virus orherpesviruses.

The crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate according to the invention ispreferably combined with and used in combination with acetylsalicylicacid, trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir,aciclovir, penciclovir, valaciclovir, famciclovir and/or valganciclovir.Especially preferred are combinations with acetylsalicylic acid oraciclovir or penciclovir or acetylsalicylic acid and aciclovir oracetylsalicylic acid and penciclovir.

The inventive mono mesylate monohydrate or the afore-mentioned drugcombinations are preferably used for the manufacture of a pharmaceuticalcomposition for the treatment and/or prophylaxis of infectious diseasesand the prevention of transmission of an infectious disease andespecially infectious diseases caused by herpes simplex viruses.

The crystalline N-[5-(amino- sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomesylate monohydrate obtainable according to the above disclosedsynthesis is then used to prepare a pharmaceutical composition thereof,wherein the crystalline N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomesylate monohydrate has the particle size distribution (PSD), specificsurface area (SSA) and particle size range (PSR) as defined herein. Tothis pharmaceutical composition acetylsalicylic acid, trifluridine,idoxuridine, foscarnet, cidofovir, ganciclovir, aciclovir, penciclovir,and/or their respective prodrugs valaciclovir, famciclovir and/orvalganciclovir might be added. Some suppliers use the name acyclovirinstead of aciclovir. Moreover, these pharmaceutical compositions arepreferably solid pharmaceutical compositions without solvents, diluents,or liquids exhibiting solubilizing properties for the activepharmaceutical ingredient (hereinafter abbreviated API) so that theparticles are not dissolved and remain unaltered in regard to theirparticle size distribution, particle size range and specific surfacearea.

As used herein, the acronym “API” ever denotes the crystallineN-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomesylate monohydrate salt.

In WO2006/103011A a wet granulation process for tablet preparation isdescribed for the free base form using diverse acids includingmethanesulfonic acid. In a series of crystallization experimentsstarting from N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide and benzoicacid, lactic acid, and sulphuric acid, a crystalline salt (apparentlyoccurring in different polymorphic forms) could only be isolated withsulphuric acid. Nevertheless, using sulphuric acid in the wetgranulation process resulted in a tablet exhibiting unfavorabledissolution properties (see Table 3 of WO2006/103011A). Repeating thewet granulation process (cf. example 5 of WO2006/103011A) using 1equivalent methanesulfonic acid as acidic component resulted in agranulate, which contained a mixture of the crystalline free base formand mesylate monohydrate salt (ca. 90:10, detectable by comparison ofthe X-ray powder diffraction spectra, which did not change significantlyover 4 weeks at 40° C. (see FIG. 1). This mesylate/free base mixture hadbeen found unsuitable for a tablet formulation, because of lowsolubility and dissolution behavior, the occurrence of at least fourpolymorphic forms and the additional risk of further interconversionbetween base and salt form under long term storage (also depending onthe water content and hygroscopicity of the tablet mixture). Thus, itwas very surprising that a definite mono mesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidecould be obtained and that this definite mono mesylate monohydrate saltofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidewith the characteristic PSR, PSD and SSA as disclosed herein overcameall problems of the state of the art and provided the opportunity toprepare stable, long-term stable, and pharmacologically applicablepharmaceutical compositions, which showed clear advantages for solidformulations.

For the purpose of tabletting, the flowability of a mixture ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate having the PSR, PSD and SSA as definedherein with usual pharmaceutical ingredients is improved with largerparticles and narrower particle size distribution. As particle sizedecreases, several interparticulate forces such as mechanicalinterlocking, hydrogen bonding, electrostatic, and van der Waals forcescan predominate over gravity. These forces act in the surface of theparticles and smaller particles have larger surface area in relation totheir mass than larger ones. In addition, these varying results may bedue to differences in the flowability measurement set-ups, humidity ofthe air, and/or particle properties such as original particle size. Abroad particle size distribution induces segregation that influencestabletting force, tablet weight and the content uniformity of thetablets. Broad particle size distribution causes more segregationproblems during tabletting than a granule batch with smaller sizedistribution within a defined range. Thus, due to various possibleparticle size ranges, particle size distributions and specific surfaceareas adjustable by various techniques, it was unforeseeable for theskilled person that the ranges for PSD, SSA and PSR as defined hereinare the most suitable for preparing pharmaceutical compositions.Particularly, it was unforeseeable for the skilled person that theranges for PSD, SSA and PSR of the crystalline mono mesylate monohydratesalt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide as definedherein lead to advantageous PK/PD in vivo profiles of itspharmacologically active free base form as exemplarily depicted in theFIGS. 9-13. Said Figures show exemplarily PK/PD in vivo profiles of theresultant free base form in vivo, when administered orally either assingle dose or in the form of multiple dosages as crystalline monomesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide.

The narrow particle size distribution of the crystalline form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, e.g. for a given mean particle size,they have fewer large and small particles, is advantageous for directcompression as a method of tablet manufacturing. The resulting particlesize distribution of the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, wherein the PSR, PSD and SSA is asdefined herein and preferably wherein the particle size distribution isdefined by d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9)from 70 to 400 μm with a specific surface area of the particles lessthan 1.0 m²/g, and more preferably defined by d(0.1) from 10 to 75 μm,d(0.5) from 100 to 175 μm, d(0.9) from 200 to 350 μm with a specificsurface area of the particles less than 0.3 m²/g, has physicalcharacteristics, which are particularly adapted to be able to allowmanufacturing by direct compression without a wet or dry granulationstep.

According to the invention, it is preferred that at least 65 v/v%, morepreferably at least 70 v/v %, even more preferably at least 80 v/v %,even more preferably at least 85 v/v %, even more preferably at least 90v/v %, even more preferably at least 95 v/v % and most preferred atleast 99 v/v % of crystalline N- [5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acet-amide monomethanesulfonic acid monohydrate particles fall in a particle size rangeof from 2 to 400 μm. Moreover it is preferred that 40 v/v %N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate particles fall in a particle size rangeof from 2-250 μm.

It was surprisingly found that the use of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate in particulate form, wherein the PSR,PSD and SSA is as defined herein and preferably wherein the particlesize distribution is defined by d(0.1) from 2 to 100 μm, d(0.5) from 30to 210 μm and d(0.9) from 70 to 400 μm with a specific surface area ofthe particles less than 1.0 m²/g, and more preferably defined by d(0.1)from 10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to 350 μmwith a specific surface area of the particles less than 0.3 m²/g in thefinal blend shows improved free-flowing and cohesive powdercharacteristics and displays cohesive briquetting and dry granulationbehavior, which effects are significant for efficient and robust directcompression.

If too many crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate particles are present whose particlesize is lower than about 4 μm, picking and sticking tend to be caused inthe later processing. If too many crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate particles are present whose particlesize is larger than about 400 μm, the compressibility becomes too poor.Therefore, it is observed that at least 65 v/v % of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate fall in a particle size range offrom 2 to 400 μm, wherein the particle size distribution is preferablydefined by d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9)from 70 to 400 μm with a specific surface area of the particles lessthan 1.0 m²/g, and more preferably defined by d(0.1) from 10 to 75 μm,d(0.5) from 100 to 175 μm, d(0.9) from 200 to 350 μm with a specificsurface area of the particles less than 0.3 m²/g.

When processing crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, its particle size distribution remainssubstantially unchanged, typically it remains totally unchanged. In viewof improved overall characteristics, it is preferred that at least 65v/v %, more preferably at least 70 v/v %, even more preferably at least80 v/v %, even more preferably at least 85 v/v %, even more preferablyat least 90 v/v %, even more preferably at least 95 v/v % and mostpreferred at least 99 v/v % of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate particles have the PSR, PSD and SSA asdefined herein and more preferably fall in a particle size range of from2 to 400 μm, wherein the particle size distribution is preferablydefined by d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9)from 70 to 400 μm with a specific surface area of the particles lessthan 1.0 m²/g, and still more preferably defined by d(0.1) from 10 to 75μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to 350 μm with a specificsurface area of the particles less than 0.3 m²/g.

A further advantage of the tablets according to the invention is thatthe tablet will have an optimized dissolution rate based on its particlesize distribution of the crystalline form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate which has the PSD, PSR and SSA asdefined herein and thus, the drug may be absorbed into the blood streammuch faster compared to the free base form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide or othersalts thereof as API in a tablet. Furthermore, the surprising dispersiontimes obtained with tablets according to the invention are advantageousfor swallowable tablets. In a further embodiment, the tablets accordingto the invention can be presented for dispersion in water. In respect ofthe stated above, the person skilled in the art understands that thedissolution behavior may be directly linked to resultant bioavailabilityproperties of an API in vivo. Accordingly, a high degree of absolutebioavailability may be expected based on the dissolution properties ofthe crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate in a tablet of the invention.

Accordingly, the present invention, surprisingly und unexpectedly,provides for chemically stable, orally administrable pharmaceuticalcompositions of the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate having PSD, PSR and SSA as definedherein, characterized by an absolute bioavailability of the resultantfree base form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamideof at least 40 to 90%, preferably 50 to 90%, more preferably 60 to 85%,when administered in a pharmaceutical composition of the invention.

In yet another aspect the present invention, surprisingly undunexpectedly, provides for chemically stable, orally administrablepharmaceutical compositions of the crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate having PSD, PSR and SSA as definedherein, characterized by absolute bioavailability of the resultant freebase form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamideof >40%, preferably >50%, even more preferably >70%, mostpreferred >80%, utmost preferred >90%, when administered in apharmaceutical composition of the invention.

In yet another aspect the present invention provides for pharmaceuticalcompositions as described herein, effective to achieve an absolutebioavailability of 70% ±30% of the resultant free base form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide, whenadministered as crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl] acetamide monomethanesulfonic acid monohydrate particles having PSD, PSR and SSA asdefined herein in a pharmaceutical composition containing at least 5 mg,preferably at least 10 mg, more preferably at least 20 mg, mostpreferred at least 25 mg thereof.

In yet another aspect of the invention said absolute bioavailability of70% ±30% of the resultant free base form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide is achievedin a human.

In the context of the present invention the term “bioavailability”denotes a subcategory of absorption. Bioavailability denotes thefraction of an administered oral dose of the crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate of the invention that reaches thesystemic circulation of a subject as the resultant free base form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide. Bydefinition, when a medication is administered intravenously, itsbioavailability is 100%. However, when a medication is administered viaother routes (such as orally), its bioavailability generally decreases(due to incomplete absorption and first-pass metabolism) or may varyfrom individual to individual. Bioavailability is one of the essentialtools in pharmacokinetics, as bioavailability must be considered whencalculating dosages for non-intravenous routes of administration.

The crystalline mono mesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, wherein thePSR, PSD and SSA is as defined herein, exhibits increased long termstability properties and a desired release kinetic and long termstability from pharmaceutical compositions, which is superior to othersalts of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, which areknown in the state of the art including also other mesylate salts.

As evident from FIG. 4 which shows the single-crystal X-ray structureanalysis of the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-pheny]acetamide monomethanesulfonic acid monohydrate, the salt is formed between themesylate and the protonated pyridinyl ring. Moreover, exactly one molequivalent methanesulfonic acid and one mol equivalent water isincorporated into the crystal structure, wherein the hydrogen atoms ofthe water molecule form hydrogen bridges with oxygen atoms of twodifferent mesylate molecules.

Preferred conditions for the crystallization ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate are reflected by the preparation of asuspension of the free base in about 10 vol. (vol.=L/kg of free base)ethanol/water (1:1), adding 1.15 equivalents of methanesulfonic acid at50-55° C. in less than 15 min, seeding with 0.5 mol % of final product,ageing for 1-1.5 h at 50° C. and cooling to 20-25° C. during 2.5 h.After further stirring for 1 h, the final product can be isolated byfiltration and drying in vacuo, resulting in a yield of >95%. Using thisprocedure, crystalline N-[5-(amino-sulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate having the PSR, PSD and SSA as definedherein, and preferably having a particle size range of from 2 to 400 μm,wherein the particle size distribution is preferably defined by d(0.1)from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9) from 70 to 400 μmwith a specific surface area of the particles less than 1.0 m²/g, andmore preferably defined by d(0.1) from 10 to 75 μm, d(0.5) from 100 to175 μm, d(0.9) from 200 to 350 μm with a specific surface area of theparticles less than 0.3 m²/g, in purity of >99% containing <2 ppmresidual Pd could be prepared reproducibly concerning yield, purity,polymorphic form, PSD, PSR and SSA from a supersaturated solution ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamideby crystallization under controlled conditions as described below.

Spontaneous crystallization from an over-saturated solution results in aco-precipitation of the free base. To simulate this process, a sample ofN-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate was dissolved in a mixture of ethanoland water (1:1) at 50° C. and then cooled down and stirred at 0° C. forca. 5 h. Samples of the precipitate were taken for microscopy exhibitingmainly small needles (see FIG. 3A) in contrast to the mono mesylatemonohydrate, which crystallizes as prisms (see FIG. 3B). Byinvestigating isolated needles applying ¹H NMR (nuclear magneticresonance) no mono mesylate monohydrate could be detected, thusexhibiting the existence of mainly free base form. Keeping a suspensionof this precipitate at 0° C. or at room temperature shows slow growth ofthe prisms consuming the needles (see FIG. 3C), which argues for a veryslow conversion to the mesylate salt form. This experiment demonstratesthe importance of selection of well-defined crystallization conditions.

To obtain N-[5-(amino- sulfonyl)-4-methyl-1, 3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate in the desired PSD, PSR and SSA, alsomoderate to slow stirring of this mixture and a flat cooling ramp ofthis mixture to room temperature are preferred. Furthermore, it ispreferred to add the methanesulfonic acid over 5-15 minutes at elevatedtemperature and to keep the resulting mixture at this elevatedtemperature for 1 to 2 hours after completion of the addition ofmethanesulfonic acid. The cooling to room temperature is performedwithin 2 to 3 hours and the mixture is thereafter slowly stirred foranother hour at room temperature. Then the crystals are filtered off,washed with alcohol/water and dried under vacuum at a temperaturebetween 20° C. and 60° C., preferably starting at 20° C. and ending at60° C.

A modified way to obtain N-[5-(amino-sulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate in the desired PSD, PSR and SSA appliesthe following conditions for the crystallization. Methanesulfonic acidis added at elevated temperatures, and preferably between 30° C. and 90°C., more preferably between 35° C. and 80° C., still more preferablybetween 40° C. and 70° C., still more preferably between 45° C. and 60°C. and most preferably at 50° C.-55° C. to the mixture of an organicsolvent and water containing N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide yielding asupersaturated solution of the mono mesylate monohydrate ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide. Organicsolvents which are miscible or consolute with water are preferred suchas MeOH, EtOH, n-PrOH, I-PrOH, acetonitrile, THF, acetone. Moreover itis preferred to add seed crystals of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethane-sulfonic acid monohydrate to this supersaturated mixture also atelevated temperatures like 30° C. to 90° C., preferably 35° C. to 80°C., more preferably 40° C. to 70° C., still more preferably 45° C. to60° C. and most preferably at 50° C.-55° C. Also moderate to slowstirring of this mixture and a slow cooling of this mixture to roomtemperature is preferred. Furthermore, it is preferred to add themethanesulfonic acid over 5 to 15 minutes at the elevated temperatureand to keep the resulting mixture at this elevated temperature for 0.5to 5 hour and more preferably for 1 to 2 hours after completion of theaddition of the methanesulfonic acid. The cooling to room temperature isperformed within 1 to 5 hour and preferably 2 to 3 hours and the mixtureis thereafter slowly stirred for preferably another hour at roomtemperature. Then the crystals are filtered off, washed withalcohol/water and preferably dried under vacuum at a temperature between20° C. and 60° C., preferably starting at 20° C. and ending at 60° C.

The crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate with the PSD, PSR and SSA as definedherein, exhibits optimized release kinetics from pharmaceuticalcompositions and improved bioavailability. Furthermore, storageproperties, especially the long-term stability of the API as well as ofthe pharmaceutical formulations are excellent.

X-ray powder diffraction spectra of film coated tablets (strengths 5 mg,25 mg, 100 mg, powdered for measurement in comparison to placebo) after24 months at room temperature revealed no change in crystallinity (seeFIGS. 5 to 7).

Compared to the mesylate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, themonohydrate of the mono mesylate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide, whereinthe particle size distribution is preferably defined by d(0.1) from 2 to100 μm, d(0.5) from 30 to 210 μm and d(0.9) from 70 to 400 μm with aspecific surface area of the particles less than 1.0 m²/g, and morepreferably defined by d(0.1) from 10 to 75 μm, d(0.5) from 100 to 175μm, d(0.9) from 200 to 350 μm with a specific surface area of theparticles less than 1.0 m²/g, preferably less than 0.6 m²/g, and mostpreferably less than 0.3 m²/g, surprisingly and unexpectedly has agreater thermostability of up to 170° C. A clear advantage of theN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomesylate monohydrate, wherein the PSD, PSR and SSA are as definedherein, is its proven long-term stability. Therefore, the inventiveN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono mesylate monohydrate, which is characterized by the PSD, PSR andSSA as disclosed herein, is better suited for the preparation oflong-term stable tablets compared to the free base form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide.

The crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate according to the invention is a usefulcompound for treatment and/or prophylaxis of infectious diseases and/orprevention of transmission of infectious diseases.

The crystalline N- [5-(aminosulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate is highly active against herpesvirusesand infections caused by herpesviruses and/or transmission of a herpesvirus or herpesviruses. Therefore, the inventive crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate is especially useful for thepreparation of a pharmaceutical composition for the treatment and/orprophylaxis of diseases, which are caused by herpesviruses or caused bythe transmission of a herpes virus or herpesviruses.

The inventive mono mesylate monohydrate salt is especially useful forthe treatment and/or prophylaxis of infections, which are caused byherpes simplex viruses, or for the prevention of transmission of aherpes virus or herpes viruses. Infections with herpes simplex viruses(HSV, subtype 1 and 2) are categorized into one of several distinctdisorders based on the site of infection. Orofacial herpes simplexinfection, the visible symptoms of which are colloquially called coldsores or fever blisters, affects the face and mouth. Orofacial herpes isthe most common form of infection. Genital herpes is the second commonform of a herpes simplex infection. Although genital herpes is largelybelieved to be caused by HSV-2 only, genital HSV-1 infections areincreasing. Other disorders such as herpetic whitlow, herpesgladiatorum, ocular herpes (keratitis), cerebral herpes infectionencephalitis, Mollaret's meningitis, neonatal herpes, and possiblyBell's palsy are also caused by herpes simplex viruses.

The inventive mono mesylate monohydrate salt is thus useful for thetreatment and/or prophylaxis of infections, which are caused by herpessimplex viruses and/or for the prevention of transmission of herpessimplex viruses.

The mono mesylate monohydrate salt of the present invention can becombined and administered together with an anti-inflammatory agent suchas acetylsalicylic acid and acetaminophen. Thus, combinations of theinventive mono mesylate monohydrate with acetylsalicylic acid and/oracetaminophen as well as pharmaceutical compositions containing such acombination are preferred.

Furthermore, the inventive mono mesylate monohydrate can be combined andcan be used in combination with an anti-viral agent. The anti-viralagent is preferably an antimetabolite and most preferably a nucleobaseanalogue, nucleotide analogue or nucleoside analogue drug. It is furtherpreferred if the anti-viral agent is useful against herpesviruses and/oragainst transmission of a herpes virus or herpes viruses and is selectedfrom the group of drugs comprising but not limited to or consisting of:trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, acicloviror penciclovir or the respective prodrugs valaciclovir, famciclovir orvalganciclovir.

The combination of the inventive mono mesylate monohydrate and a furtheractive agent like an anti-inflammatory, immunomodulatory, or anti-viralagent, such as therapeutic vaccines, siRNAs, antisense oligonucleotides,nanoparticles or virus-uptake inhibitors such as n-docosanol, may beadministered simultaneously in one single pharmaceutical composition orin more than one pharmaceutical composition, wherein each compositioncomprises at least one active agent.

The pharmaceutical compositions of the present invention can be preparedin a conventional solid and a conventional pharmaceutically-madeadjuvant at suitable dosage level in a known way. Preferred preparationsmay be adapted for oral application. These administration forms include,for example, pills, tablets, film tablets, coated tablets, sustainedrelease formulations, and capsules.

The pharmaceutical compositions according to the invention preferablycomprise 5 to 70% by weight more preferably 10 to 30% by weightcrystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl] acet-amide monomethanesulfonic acid monohydrate (all percentage data are percentages byweight based on the weight of the pharmaceutical preparation), whereinthe PSD, PSR and SSA is as defined herein. The pharmaceuticalcomposition comprises usually 2 to 600 mg of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate, preferably 5 to 500 mg, morepreferably 10 to 300 mg and particularly preferably 20 to 200 mg,wherein PSD, PSR and SSA is as disclosed above.

The pharmaceutical composition according to the invention optionallycomprises one or more filler, which, for example, are selected from thegroup consisting of: microcrystalline cellulose, fiber cellulose,calcium phosphates and mannitol. Preferably, according to the invention,microcrystalline cellulose and mannitol are used. The pharmaceuticalcomposition expediently comprises 20 to 80%, preferably 40 to 80%,particularly preferably 45 to 70% microcrystalline cellulose and 1 to40%, preferably 5 to 30%, particularly preferably 10 to 20% mannitol.The pharmaceutical preparation according to the invention may compriseat least one disintegration auxiliary, which is, for example, selectedfrom the group consisting of starch, pre-gelatinized starch, starchglycolates, cross-linked polyvinylpyrrolidone, sodiumcarboxymethylcellulose (=croscarmellose sodium) and other salts ofcarboxymethylcellulose. A mixture of two disintegration agents can alsobe used. According to the invention, the use of croscarmellose sodium ispreferred. The pharmaceutical composition expediently comprises 3 to35%, preferably 5 to 30% and particularly preferably 5 to 10% of thedisintegration auxiliary(ies). The pharmaceutical composition of theinvention may comprise at least one lubricant selected from the groupconsisting of fatty acids and their salts. According to the invention,the use of magnesium stearate is particularly preferred.

The pharmaceutical composition of the invention may comprise a flowagent, which could be colloidas anhydrous silica or talcum powder.According to the invention, the use of colloidas anhydrous silica isparticularly preferred. The flow agent is expediently used in an amountof 0.3 to 2.0%, particularly preferably from 0.4 to 1.5% and mostpreferably from 0.5 to 1%.

A particularly preferred pharmaceutical composition of the inventioncomprises: 5%-30% crystalline N- [5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate, wherein the PSD, PSR and SSA is asdefined herein and preferably the particle size distribution is definedby d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9) from 70to 400 μm with a specific surface area of the particles less than 1.0m²/g, and more preferably defined by d(0.1) from 10 to 75 μm, d(0.5)from 100 to 175 μm, d(0.9) from 200 to 350 μm with a specific surfacearea of the particles less than 0.3 m²/g, 5%-10% croscarmellose-sodium,0.5 to 0.7% magnesium stearate, 40%-70% microcrystalline cellulose,10%-20% mannitol and 0.5% to 1% colloidal anhydrous silica.

Further pharmaceutical compositions according to the inventionpreferably comprise 30 to 90% more preferably 50 to 70% by weightcrystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acet-amide monomethanesulfonic acid monohydrate, wherein the PSD, PSR and SSA is asdefined herein and preferably the particle size distribution is definedby d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9) from 70to 400 μm with a specific surface area of the particles less than 1.0m²/g, and more preferably defined by d(0.1) from 10 to 75 μm, d(0.5)from 100 to 175 μm, d(0.9) from 200 to 350 μm with a specific surfacearea of the particles less than 0.3 m²/g (all percentage data arepercentages by weight based on the weight of the pharmaceuticalpreparations). The pharmaceutical composition comprises usually 20 to750 mg as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, wherein the PSD, PSR and SSA is asdefined herein and preferably 50 to 500 mg as free base equivalent andparticularly preferably 50 to 250 mg as free base equivalent based on asingle dosage.

As used herein for the specification and the claims, the givenmg-dosages for the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate as API in a pharmaceutical compositionof the invention, particularly for tablet formulations are everdescribed as the free base equivalent dosage, which means that thecontent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate is approximately 1.3 times higher asindicated. This is due to the fact that the pharmacologically activeform in vivo is the free base form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide,which is however administered as the mono mesylate monohydrate salt formhaving the characteristic PSD, PSR and SSA of the invention.

Therefore, the term “free base equivalent” as used herein and in theclaims denotes the dosage of the pharmacologically active form, thuscalculated as free base form of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide.

The pharmaceutical composition according to the invention optionallycomprises one or more dry binders, which, for example, are selected fromthe group consisting of microcrystalline cellulose, fiber cellulose,calcium phosphates, and mannitol. Preferably, microcrystalline celluloseis used. This is commercially available under the designation AvicelB,for example. The pharmaceutical composition expediently comprises 1 to20%, preferably 1 to 10%, particularly preferably 1 to 5% of the drybinder(s). The pharmaceutical preparation according to the invention maycomprise at least one disintegration auxiliary which is for exampleselected from the group consisting of starch, pre-gelatinized starch,starch glycolates, cross-linked polyvinylpyrrolidone, sodiumcarboxymethylcellulose (=croscarmellose sodium) and other salts ofcarboxy-methylcellulose. A mixture of two disintegration agents can alsobe used. The use of croscarmellose sodium and cross-linkedpolyvinylpyrrolidone or a mixture of the two is preferred. Thepharmaceutical composition expediently comprises 3 to 35%, preferably 10to 30% and particularly preferably 15 to 25% of the disintegrationauxiliary(ies). The pharmaceutical preparation of the invention maycomprise at least one lubricant selected from the group consisting offatty acids and their salts. The use of magnesium stearate isparticularly preferred.

A pharmaceutical composition for a tablet with 25 mg of the activepharmacologic ingredient (calculated as free base form) comprises 32.3mg of crystalline N-[5-(aminosulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, wherein the PSD, PSR and SSA is asdefined herein and preferably the particle size distribution is definedby d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9) from 70to 400 μm with a specific surface area of the particles less than 1.0m²/g, and more preferably defined by d(0.1) from 10 to 75 μm, d(0.5)from 100 to 175 μm, d(0.9) from 200 to 350 μm with a specific surfacearea of the particles less than 0.3 m²/g, 60.9 mg of microcrystallinecellulose, 9.8 mg of croscarmellose sodium, 20.0 mg of mannitol, 1.3 mgof colloidal anhydrous silica, and 0.9 mg of magnesium stearate. Thetotal weight of the blend is 125.0 mg.

A further pharmaceutical composition for a tablet with 100 mg of theactive pharmacologic ingredient (calculated as free base form) comprises129.0 mg of the inventive crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acet-amidemono methanesulfonic acid monohydrate, 243.4 mg of microcrystallinecellulose, 39.0 mg of croscarmellose sodium, 80.1 mg of mannitol, 5.0 mgof colloidal anhydrous silica, and 3.5 mg of magnesium stearate. Thetotal weight of the blend is 500.0 mg.

Furthermore, the present invention also includes pharmaceuticalcompositions for sublingual application, which preparations in additionto typical vehicles contain at least crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate, wherein the PSD, PSR and SSA isas defined herein, as active ingredient.

An inventive pharmaceutical composition may contain the followingpreservatives: phenoxyethanol, formaldehyde solution, parabens,pentanediol, or sorbic acid.

As pharmaceutically acceptable carrier, excipient and/or diluents can beused carriers such as preferably an inert carrier like lactose, starch,sucrose, cellulose, magnesium stearate, dicalcium phosphate, calciumsulfate, talc, mannitol, ethyl alcohol (liquid filled capsules);suitable binders include starch, gelatin, natural sugars, cornsweeteners, natural and synthetic gums such as acacia, sodium alginate,carboxymethylcellulose, polyethylene glycol and waxes, sugars such assucrose, starches derived from wheat corn rice and potato, natural gumssuch as acacia, gelatin and tragacanth, derivatives of seaweed such asalginic acid, sodium alginate and ammonium calcium alginate, cellulosematerials such as methylcellulose, sodium carboxymethylcellulose andhydroxypropylmethylcellulose, polyvinylpyrrolidone, and inorganiccompounds such as magnesium aluminum silicate; lubricants such as boricacid, sodium benzoate, sodium acetate, sodium chloride, magnesiumstearate, calcium stearate, or potassium stearate, stearic acid, highmelting point waxes, and other water soluble lubricants such as sodiumchloride, sodium benzoate, sodium acetate, sodium oleate, polyethyleneglycols and D,L-leucine; disintegrating agents (disintegrates) such asstarch, methylcellulose, guar gum, modified starches such as sodiumcarboxymethyl starch, natural and synthetic gums such as locust bean,karaya, guar, tragacanth and agar, cellulose derivatives such asmethylcellulose and sodium carboxy-methylcellulose, microcrystallinecelluloses, and cross-linked microcrystalline celluloses such as sodiumcroscarmellose, alginates such as alginic acid and sodium alginate,clays such as bentonites, and effervescent mixtures; coloring agents,sweetening agents, flavoring agents, preservatives; glidents are forexample silicon dioxide and talc; suitable adsorbent are clay, aluminumoxide, suitable diluents are water or water/propylene glycol solutionsfor parenteral injections, juice, sugars such as lactose, sucrose,mannitol, and sorbitol, starches derived from wheat, corn rice, andpotato, and celluloses such as microcrystalline cellulose.

The following examples are included to demonstrate preferred embodimentsof the invention. It should be appreciated by those of skill in the artthat the techniques disclosed in the examples, which follow, representtechniques discovered by the inventor to function well in the practiceof the invention, and thus can be considered to constitute preferredmodes for its practice. However, those of skill in the art should, inlight of the present disclosure, appreciate that many changes can bemade in the specific embodiments which are disclosed and still obtain alike or similar result without departing from the spirit and scope ofthe invention.

The pharmaceutical compositions according to the invention can beadministered to a patient in need thereof at a once daily dose of about20 to 750 mg as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate, wherein the PSD, PSR and SSA isas defined herein and preferably the particle size distribution isdefined by d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9)from 70 to 400 μm with a specific surface area of the particles lessthan 1.0 m²/g, and more preferably defined by d(0.1) from 10 to 75 μm,d(0.5) from 100 to 175 μm, d(0.9) from 200 to 350 μm with a specificsurface area of the particles less than 0.3 m²/g, preferably of about 50to 500 mg as free base equivalent and even more preferably of about 50to 250 mg as free base equivalent based on a single dosage. Thepharmaceutical compositions according to the invention can also beadministered to a patient in need thereof thrice daily, twice daily,once daily, thrice weekly, twice weekly, or once weekly. Theadministration on a thrice weekly, twice weekly, or once weekly basis ispreferred and especially preferred is a once weekly administration, i.e.an administration one time a week of a pharmaceutical compositioncontaining between 400 mg to 500 mg as free base equivalent of theinventive N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acet-amide monomethanesulfonic acid monohydrate. Moreover it is preferred to start theadministration of the mono mesylate monohydrate of the present inventionwith a high loading dose, for instance, with an initial single dose of400 mg to 800 mg as free base equivalent and to continue theadministration with a lower dose of 100 mg to 150 mg as free baseequivalent per day or per week over the period of treatment.

Particularly, the definite crystalline mono mesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide with thecharacteristic PSR, PSD and SSA as disclosed herein exhibitscharacteristic PK/PD profiles in vivo as the free base form whenadministered in a pharmaceutical composition in accordance with theinvention.

Exposure of the free base form of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide to thehuman body may be measured by high pressure liquid chromatography (HPLC)by looking at different pharmacokinetic parameters in suitable bodilyfluids such as for instance blood plasma and urine, the most commonparameters being the C_(max), the so-called area under the curve (AUC),and the terminal half-life (t_(1/2z)). Hereto, the person skilled in theart understands that said parameters are determined by using adequatebioanalytical methods with adequate sensitivity, specificity,ruggedness, stability and repeatability, as for instance a qualifiedliquid chromatography triple quad mass spectrometry based method coupledwith a suitable extraction method for the separation of the analytefrom, e.g. the blood plasma. For example, AUC values may be calculatedfrom 0-24 hours using the trapezoid method.

For instance, after administration of crystalline mono mesylatemonohydrate salt of N-[5-(aminosulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide, itsconcentration in the blood increases in the form of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide until itreaches a peak concentration, which measured in blood by a suitable HPLCmethod is the C_(max) and the time taken to reach the C_(max), is termedt_(max). The area under the blood plasma concentration curve (area underthe curve abbreviated as AUC) is another useful measurement andrepresents the drug exposure of the free base in the systemiccirculation over a period of time; e.g. 0-24 h or 0-∞.

The mean C_(max), values are derived from averaging the highest observedfree base concentration ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidefor all members of a subject group under investigation.

The mean C_(max,ss) values are derived from averaging the highestobserved free base concentration at steady state ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide for allmembers of a subject group under investigation.

In a specific aspect the present invention provides for a pharmaceuticalcomposition as described above for the crystalline mono mesylatemonohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide, effectiveto achieve a mean maximum blood plasma concentration (mean C_(max)) ofthe free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide in asubject of at least one of

-   -   a) 608±184 ng/ml for a 40 mg dosage as free base equivalent of        crystalline N- [5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, said dosage being a        single oral dose administered;    -   b) 1306±125 ng/ml for a 80 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, said dosage being a        single oral dose administered;    -   c) 2613±1341 ng/ml for a 160 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl- 1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, said dosage being a        single oral dose administered;    -   d) 3600±752 ng/ml for a 240 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, said dosage being a        single oral dose administered;    -   e) 4648±1813 ng/ml for a 320 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, said dosage being a        single oral dose administered;    -   f) 6926±1656 ng/ml for a 400 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, said dosage being a        single oral dose administered;    -   g) 6921±2190 ng/ml for a 480 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, said dosage being a        single oral dose administered.

In yet another specific aspect the present invention provides for apharmaceutical composition as described above for the crystalline monomesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-p yridinyl)-phenyl]acetamide, effectiveto achieve a mean maximum blood plasma concentration (mean C_(max)) ofthe free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl] in a subject of atleast one of

-   -   a) 608±184 ng/ml for a 40 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or effective to        achieve an AUC_(0-24h) of 10090±3114 ng-h/ml in a subject for a        40 mg dosage as free base equivalent of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, and wherein t_(1/2z) is        72±3 h on average; said dosage being a single oral dose        administered;    -   b) 1306±125 ng/ml for a 80 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or effective to        achieve an AUCo_(24h) of 21940±2057 ng-h/ml in a subject for a        80 mg dosage as free base equivalent of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, and wherein t_(1/2z) is        74±5 h on average; said dosage being a single oral dose        administered;    -   c) 2613±1341 ng/ml for a 160 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or effective to a        achieve an AUC_(0-24h) of 40470±16700 ng-h/ml in a subject for a        160 mg dosage as free base equivalent of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, and wherein t_(1/2z) is        63±6 h on average; said dosage being a single oral dose        administered;    -   d) 3600±752 ng/ml for a 240 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or effective to        achieve an AUCo_(24h) of 59610±12770 ng-h/ml in a subject for a        240 mg dosage as free base equivalent of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, and wherein t_(1/2z) is        64±5 h on average; said dosage being a single oral dose        administered;    -   e) 4648±1813 ng/ml for a 320 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or effective to        achieve an AUC_(0-24h) of 76250±27630 ng-h/ml in a subject for a        320 mg dosage as free base equivalent of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, and wherein t_(1/2z) is        57±3 h on average; said dosage being a single oral dose        administered;    -   f) 6926±1656 ng/ml for a 400 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or effective to        achieve an AUC_(0-24h) of 104800±25740 ng-h/ml in a subject for        a 400 mg dosage as free base equivalent of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, and wherein t_(1/2z) is        57±4 h on average; said dosage being a single oral dose        administered;    -   g) 6921±2190 ng/ml for a 480 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl) -4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or effective to        achieve an AUC_(0-24h) of 112800±34260 ng-h/ml in a subject for        a 480 mg dosage as free base equivalent of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, and wherein t_(1/2z) is        53±4 h on average; said dosage being a single oral dose        administered.

In yet another specific aspect the present invention provides for apharmaceutical composition as described above for the crystalline monomesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide, effectiveto achieve a mean maximum blood plasma concentration at steady state(mean C_(max,ss)) of the free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide in asubject of at least one of

-   -   a) 1358±167 ng/ml for a 25 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, said dosage being a        steady state dose achieved after once daily single doses        administered for 21 days;    -   b) 6358±1701 ng/ml for a 100 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, said dosage being a        steady state dose achieved after once daily single doses        administered for 21 days;    -   c) 9987±2608 ng/ml for a 200 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, said dosage being a        steady state dose achieved after once daily single doses        administered for 21 days.

In yet another specific aspect the present invention provides for apharmaceutical composition as described above for the crystalline monomesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide, effectiveto achieve a mean maximum blood plasma concentration at steady state(mean C_(max,ss)) of the free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide in asubject of at least one of

-   -   a) 1358±167 ng/ml for a 25 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or effective to        achieve an AUC_(tss) of 23430±3020 ng-h/ml in a subject for a 25        mg dosage as free base equivalent of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, and wherein t_(1/2z) is        69±6 h on average, said dosage being a steady state dose        achieved after once daily single doses administered for 21 days;    -   b) 6358±1701 ng/ml for a 100 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or effective to        achieve an AUC_(t,ss) of 108800±28610 ng-h/ml in a subject for a        100 mg dosage as free base equivalent of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, and wherein t_(1/2z) is        60±4 h on average, said dosage being a steady state dose        achieved after once daily single doses administered for 21 days;    -   c) 9987±2608 ng/ml for a 200 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or effective to        achieve an AUC_(t,ss) of 168500±37970 ng-h/ml in a subject for a        200 mg dosage as free base equivalent of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, and wherein t_(1/2z) is        57.19±5.451 h on average, said dosage being a steady state dose        achieved after once daily single doses administered for 21 days.

In yet another specific aspect the present invention provides for amethod of treatment and/or prophylaxis of an infectious disease and/orprevention of transmission of an infectious disease wherein a meanmaximum blood plasma concentration (mean C_(max)) of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide of at leastone of

-   -   a) 608±184 ng/ml for a 40 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or an AUC_(0-24h) of        10090±3114 ng-h/ml for a 40 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, wherein t_(1/2z) is 72±3        h on average;    -   b) 1306±125 ng/ml for a 80 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or an AUC_(0-24h) of        21940±2057 ng-h/ml for a 80 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, wherein t_(1/2z) is 74±5        h on average;    -   c) 2613±1341 ng/ml for a 160 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl- 1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or an AUC_(0-24h) of        40470±16700 ng-h/ml for a 160 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, wherein t_(1/2z) is 63±6        h on average;    -   d) 3600±752 ng/ml for a 240 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl- 1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or an AUC_(0-24h) of        59610±12770 ng-h/ml for a 240 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-p yridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, wherein t_(1/2z) is 64±5        h on average;    -   e) 4648±1813 ng/ml for a 320 mg dosage as free base equivalent        of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or an AUC_(0-24h) of        76250±27630 ng-h/ml for a 320 mg dosage as free base equivalent        of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-p yridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, wherein t_(1/2z) is 57±3        h on average;

f) 6926±1656 ng/ml for a 400 mg dosage as free base equivalent ofcrystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate and/or an AUC_(0-24h) of 104800±25740ng-h/ml for a 400 mg dosage as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, wherein t_(1/2z) is 57±4 h on average;

g) 6921±2190 ng/ml for a 480 mg dosage as free base equivalent ofcrystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate and/or an AUC_(0-24h) of112800±34260 ng-h/ml for a 480 mg dosage as free base equivalent ofcrystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, wherein t_(1/2z) is 53±4 h on average,is achieved in a human; and wherein said dosage is a single oral doseadministered.

In yet another specific aspect the present invention provides for amethod of treatment and/or prophylaxis of an infectious disease and/orprevention of transmission of an infectious disease wherein a meanmaximum blood plasma concentration at steady state (mean C_(max,ss)) ofthe free base of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide of at leastone of

-   -   a) 1358±167 ng/ml for a 25 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl- 1,3        -thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide mono        methanesulfonic acid monohydrate and/or an AUC_(t,ss) of        23430±3020 ng-h/ml for a 25 mg dosage as free base equivalent of        crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, wherein t_(1/2z) is 69±6        h on average;    -   b) 6358±1701 ng/ml for a 100 mg dosage as free base equivalent        of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or an AUC_(t,ss) of        108800±28610 ng-h/ml in a subject for a 100 mg dosage as free        base equivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,        3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, wherein t_(1/2z) is 60±4        h on average;    -   c) 9987±2608 ng/ml for a 200 mg dosage as free base equivalent        of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate and/or effective to        achieve an AUC_(t,ss) of 168500±37970 ng-h/ml in a subject for a        200 mg dosage as free base equivalent of crystalline        N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide        mono methanesulfonic acid monohydrate, and wherein t_(1/2z) is        57.19±5.451 hon average, is achieved in a human; and wherein        said dosage is a steady state dose achieved after once daily        single doses administered for 21 days.

In yet another specific aspect of the invention said mean maximum bloodplasma concentration (mean C_(max)) of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide is achievedin a human.

In yet another specific aspect of the invention said mean maximum bloodplasma concentration at steady state (mean C_(max,ss)) of the free baseof N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide is achievedin a human.

In yet another specific aspect of the invention said AUC_(0-24h),AUC_(0-∞)and t_(1/2z) is achieved in a human.

In yet another specific aspect of the invention said AUC_(t,ss) andt_(1/2z) is achieved in a human.

As used in the specification and the claims “AUC_(t,ss)” denotes thearea under the analyte versus time concentration curve over a dosinginterval (tau) at steady-state (ss), calculated by linear up/log downsummation.

As used in the specification, the general expression “AUC_(t1-t2)”denotes the area under the analyte versus time concentration curve frompoint in time t₁ to point in time t₂, calculated by linear up/log downsummation. For example AUC₀₋₂₄ denotes the area under the analyte versustime concentration curve from point in time of administration (t₁=0) tothe point in time of 24h after administration (t₂=24h). Accordingly,AUC_(0-∞)denotes the concentration from time of administration up toinfinity, calculated as

${{AUC}_{0 - \infty} = {{AUC}_{0 - {last}} + \frac{C_{last}}{\lambda_{z}}}},$

wherein AUC_(0-last) is defined as the area under the analyte vs. timeconcentration up to time of the last qualifiable concentration,calculated by linear up/log down summation and C_(last) is defined aslast quantifiable observed analyte concentration. λ_(z) is the apparentterminal elimination rate constant, determined by linear regression ofterminal points of In-linear analyte concentration-time curve.

C_(max) is the maximal observed analyte concentration and t_(max) is thetime to reach C_(max); t_(1/2z) is defined as the apparent terminalelimination half-life, calculated as

${t_{1\text{/}2z} = \frac{\ln (2)}{\lambda_{z}}},$

wherein λ_(z) is defined as above.

As used in the specification and the claims “t_(i/2z)” denotes theapparent terminal elimination half-life calculated as:t_(1/2z)=0.693/λ_(z) Thereby, λ_(z) denotes the apparent terminalelimination rate constant.

Further, it should be noted that the crystalline mono mesylatemonohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide of theinvention is used as API for tablet formulation in accordance with theinvention, whereas the free base form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide, having theformula

is the resultant pharmacologically active form in the body of a subjectafter administration of crystalline mono mesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide, preferablyafter oral administration thereof.

Further, the person skilled in the art understands that thepharmaceutical compositions of the invention among each other comprisephysical or chemical dosage form characteristics, which may modulateeither one of said mean C_(max), AUC_(0-24h), AUC_(t,ss), AUC_(0-∞), andt_(1/2z) as given in the above specific aspects of the invention.

Further, in accordance with the invention the person skilled in the artunderstands that food intake prior to administration of the crystallinemono mesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide of asubject may influence positively the in vivo PK/PD profile of theresultant free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide.Thus, in accordance with the invention a decreased absorption rate and adelayed t_(max) of the resultant free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide may beexpected in fasted subjects after administration of crystalline monomesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide.

By contrast, food intake prior to administration of crystalline monomesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidemay lead to an increase in mean C_(max) of at least about 25% and anincrease in AUC of at least about 10% of the resultant free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide in humanblood plasma when measured by suitable HPLC method. Thereby t_(1/2z)remains constant.

In accordance with the invention, the administration of crystalline monomesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamidewith the free base equivalent dosages as disclosed herein is safe andwell tolerated by a subject in need thereof. No dose-dependent adverseevents are to be expected when crystalline mono mesylate monohydratesalt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamideis administered as disclosed herein.

Further modifications and alternative embodiments of various aspects ofthe invention will be apparent to those skilled in the art in view ofthis description. Accordingly, this description is to be construed asmere illustrative and is for the purpose of teaching those skilled inthe art the general manner of carrying out the invention. It is to beunderstood that the forms of the invention shown and described hereinare to be taken as examples of embodiments. Elements and materials maybe substituted for those illustrated and described herein, parts andprocesses may be reversed, and certain features of the invention may beutilized independently, all as would be apparent to one skilled in theart after having the benefit of this description of the invention.Changes may be made in the elements described herein without departingfrom the spirit and scope of the invention as described in the followingclaims.

EXAMPLES Example 1

Synthesis of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate particles having the inventive PSD, PSRand SSA

Step 1 (Suzuki-Miyaura coupling and saponification) The inertizedreactor is charged with bis(triphenylphosphine)palladium(II) chloride(0.010 eq.) and reinertized. Then, toluene (1.65 vol.) is added. Afterheating to 40° C., triethylamine (3.00 eq.) is added. A solution ofethyl-4-bromophenylacetate (1.00 eq.) in toluene (0.82 vol.) is added.The resulting suspension is heated to 90-95° C. prior to dosing pinacolborane (1.30 eq.) over a period of 60-90 min. Stirring at 90-95° C. iscontinued for at least 2 more h before conversion is checked by HPLC.After cooling to 10° C., 2-chloropyridine (1.00 eq.) is charged to thereaction mixture. Then, 30% NaOH (6.00 eq.) is added followed by heatingto 55-60° C. Stirring at this temperature is continued for at least 4 hbefore conversion is checked by HPLC. Once conversion is deemedcomplete, the reaction mixture is concentrated at about 300 mbar until0.8 vol. (vol. refers to kg of starting material (=1.00 eq) in therespective step, i.e. L/kg starting material) of distillate have beencollected. The reaction mixture is diluted with water (2.72 vol.),cooled to 20° C. and the phases are separated. The organic layer isdiscarded, while the pH of the aqueous layer is adjusted to pH 1 byaddition of 33% HCl at 20° C. MIBK (2.30 vol.) and Celite (165 g/kg) areadded and the resulting mixture is stirred for at least 15 min at 20° C.before the solids are removed by filtration. The reactor and the filtercake are rinsed successively with water and the combined filtrate istransferred back into the reactor. The phases are separated and theaqueous layer is washed twice more with MIBK. After dilution with water,the aqueous acidic product solution was heated to 55° C. and filteredthrough a plug packed with Celite at the bottom and activated charcoalon top. The Celite/charcoal plug was washed once more with pre-heatedwater (0.5 vol., 55° C.) and the combined filtrate was charged back intothe reactor. At 20° C., the pH was adjusted to ˜3.0 by addition of 30%NaOH before the product solution was heated to 60° C. More NaOH wasdosed to adjust the pH to 4.1-4.3. The resulting suspension was stirredfor 1-1.5 h at 60° C. prior to being cooled to 20° C. After additionalstirring for at least 1 h at this temperature, the product was filtered,washed twice with water, pre-dried in a flow of N₂ and finally dried invacuum at 50-65° C. Typical yield: 38-41%.

Step 2 (amide coupling)

The reactor is charged with product from step 1 (1.00 eq.) and4-methyl-2-(methylamino)-1, 3-thiazole-5-sulfonamide (1.02 eq.). THF(7.08 vol.) and NMP (1.11 vol.) are added. The resulting suspension iscooled to 0° C. prior to adding1-ethyl-3-(3-dimethyllaminopropyl)carbodiimide hydrochloride (1.23 eq.)in 4 equal portions over a period of >90 min. After at least 2 more h at0° C., the reaction mixture is warmed to 20° C. At this temperature,stirring is continued for additional 2 h before conversion is checked byHPLC. Then, at 10-15° C. about 2% (0.2 vol.) of the reaction mixture areadded to water (12.3 vol.) within at least 5 min. The resulting thinsuspension is stirred at 10-15° C. for at least 1 h prior to dosage ofthe remaining bulk of the reaction mixture over >4 h. Stirring at 10-15°C. is continued for at least 0.5 h before the solids are filtered off,washed with water and dried on a nutsche filter in a steady flow of N₂until deemed sufficiently dry (LOD<45% w/w; LOD: Loss on drying).

The feed reactor is charged with the crude product, THF (8.15 vol.), andwater (up to 1.17 vol. depending on the loss on drying of crudeproduct). The resulting suspension is heated to 60-65 ° C. and stirredfor 1 h at this temperature. An almost clear solution is obtained whichis subjected to polish filtration using a heatable lense filter heatedto 60° C. The feed reactor, the transfer lines and the filter aresuccessively rinsed with a mixture of THF (0.44 vol.) and purified water(0.06 vol.) at 60-65° C. The combined filtrate is collected in aseparate reactor and heated to 50-55° C. To the reactor content, water(3.23 vol.) is dosed over at least 30 min. Stirring at 50-55° C. iscontinued for 1-1.5 h before another portion of water (8.93 vol.) isslowly added within 2 h. After stirring for 1-1.5 h at 50° C., theresulting suspension is cooled to 5° C. over 2.5 h and stirred forfurther 0.5 h. Then, the solids are filtered off, washed with water(3×2.96 vol.) and pre-dried on the nutsche filter in a steady flow ofN₂. Final drying is accomplished in vacuo at 50-65° C. using a conicaldrier. Typical yield: 78-83%.

Step 3 (Salt Formation) The reactor is charged with product from step 2(1.00 eq.), ethanol (4.96 vol.) and water (4.96 vol.). After heating theresulting suspension to 50-55° C., methanesulfonic acid (1.15 eq.) isadded within <15 min. Complete dissolution of starting materials istypically observed at the very end of addition. Immediately within thenext 5 min, stirring is reduced to the minimum acceptable rate and thereaction mixture is seeded with N-[5-(aminosulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl] acetamide monomethanesulfonic acid monohydrate (0.005 eq.) which was prepared in thedesired polymorphic form in a preceding experiment. Slow stirring at50-55° C. is continued for 60 to 90 min prior to cooling down to 20 to25° C. during >2.5 h. After stirring for 1 more h, the solids arefiltered off, washed with ethanol/water 5:2 V/V (3.10 vol.), pre-driedin a nitrogen flow and transferred into a conical drier for final dryingin vacuo at 20 to 60° C. Typical yield: >95%.

Particle Analysis and Detection A Malvern Mastersizer 2000 with adispersion unit Malvern Hydro 2000S was used for liquid dispersion.Dispersing agent was Span^(TM) 80 used at a concentration of 0.1%(volume/volume) in n-heptane. Stirring rate was 2,500 rounds per minute.Typically, a slurry of 50 milligrams ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidemono methanesulfonic acid monohydrate was prepared in a vial containing4 to 5 mL dispersant. Should any agglomerates have occurred, then thesewere converted to primary particles by ultrasonic treatment for 10seconds. Those with ordinary skills in the art may recognize thatultrasonic treatment is common practice in converting agglomerates tosmaller particles. Once the suspension had been generated, thesuspension was transferred to the Malvern Mastersizer 2000 with adispersion unit Hydro 2000S by pipetting, until an optimal concentrationrange had been reached. The optimal concentration range was assessed bythe obscuration value displayed by the Malvern Mastersizer 2000.Typically, optimal obscuration values are in the range from about 10 toabout 20 percent. Then, the measurement was performed with automaticsubtraction of the background. Data were analyzed automatically usingthe Fraunhofer diffraction equation. For microscopy, either the slurryused for particle size analysis or a new batch was used. The size of theobserved particles was determined by means of the software analySISstart 5.0 (Olympus Soft Imaging Solutions GmbH). The procedure describedabove complies with USP 429 (light diffraction measurement of particlesize) and Ph. Eur. 2.9.31 (particle size analysis by laser lightdiffraction). In addition to particle size analysis by laser lightdiffraction, an optical investigation using a microscope was conducted.In case of release measurements, system suitability testing must beperformed prior to dispersing, which is common practice for thoseskilled in the art.

Example 2

The trials disclosed by example 2 were conducted in order to investigatethe influence of the particle size distribution (PSD) of the API on thedissolution properties of the tablet cores.

The term “particle size distribution” of a powder, or granular material,or particles dispersed in fluid, as used within this application, is alist of values or a mathematical function that defines the relativeamounts of particles present, sorted according to size. The d(0.1),d(0.5) and d(0.9) values indicate that 10%, 50% and 90% of the particlesmeasured were less than or equal to the size stated. For example, valuesof d(0.1)=52, d(0.5)=129 and d(0.9)=257 mean that 10% of the particleswere less than or equal to 52 μm, 50% were less than or equal to 129 μmand 90% were less than or equal to 257 μm (cf. Table 1, trial batchnumber G05). In order to study the dissolution properties of the tabletcores with different PSD of the inventiveN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate, 100 mg and 25 mg (calculated asfree base form; i.e. the free base equivalent thereof) tablet corescontaining the inventiveN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate in an amount of 129 mg and 32.3mg, respectively, were prepared.

Type and size of the tablet cores 100 mg tablet core, diameter 11 mm 25mg tablet core, diameter 7 mm

Equipments Blending: Bohle MC5 with glass tube

Tabletting

-   -   Kilian rotary press with chamber feed shoe    -   Tooling 100 mg dose strength: 11r11 or 12r11 with break score on        one site    -   Tooling 25 mg dose strength: 7r6

Analytics

Dissolution (1000 ml, 0.1 M HCl, paddle apparatus according to USPapparatus 2, paddle speed 50 rounds per minute, n=6)

Compounds (API) API:N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acet-amidemono methanesulfonic acid monohydrate, wherein at least 65 v/v %N-[5-(Aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]-acetamidemono methanesulfonic acid monohydrate particles fall in a particle sizerange of from 2 to 500 micrometer (μm).

G01, G02, G03, G04, G05 are five different tablet test batches of theN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acet-amidemono methanesulfonic acid monohydrate, wherein the particle size is in arange from 1 to 400 μm with a particle size distribution of d(0.1),d(0.5) and d(0.9) shown by Table 1.

TABLE 1 Particle size distribution (PSD) of different batches of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide mono methanesulfonic acid monohydrate. TrialParticle size distribution Specific batch d(0.1) d(0.5) d(0.9) surfacearea API batch number number [μm] [μm] [μm] [m²/g] BXR4FLS G01 3 51 1020.7 BXR3NC1 G02 43 118 254 0.1 NE-023932-A-4-26 crude 1#1 M1 G03 1 4 112.4 NE-023932-A-4-27 G04 22 66 143 0.2 IPC 1#1 NE-023932-batch- G05 52129 257 0.1 02-2010

Preparation of Final Blends

Five final blends (batches GO1 to G05) with the different API batcheswere prepared. The formulations of the cores (25 mg and 100 mg dosestrength, calculated as free base form) are shown in Table 2.

TABLE 2 Formulation 25 mg and 100 mg dose strength (calculated as freebase form; i.e. the free base equivalent thereof) mg per 25 mg per 100Component mg tablet mg tablet N-[5-(aminosulfonyl)-4-methyl- 32.3 (salt)129.0 (salt) 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide mono methanesulfonic acid monohydrateMicrocrystalline cellulose 60.9 243.4 Croscarmellose sodium 9.8 39.0Mannitol 20.0 80.1 Silica, colloidal anhydrous 1.3 5.0 Magnesiumstearate 0.9 3.5 Sum final blend 125.2 500.0

The final blends were prepared by sieving the raw materials using a 1.0mm sieve. N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, i.e. the API, wherein the particlesize distribution is in a range from 1 to 400 μm, microcrystallinecellulose, croscarmellose sodium, mannitol and silica colloidalanhydrous were mixed for 30 minutes in a free fall blender. Magnesiumstearate was added, and the blends were mixed for additional 5 minutes.No problems were observed during the process.

The bulk properties of batches GO1 to G05 are shown in Tables 3 and 4.

TABLE 3 Bulk properties of final blends Parameter G01 G02 G03 G04 G05Bulk density 0.413 0.435 0.385 0.403 0.440 [g/ml] Tapped density 0.5100.526 0.563 0.500 0.550 [g/ml] Flowability [cot] 1.25 1.16 0.893 1.091.28

A significant difference in bulk density was seen for batch G03. Thiswas the final blend, which contains the micronised API. Therefore, thebulk density was lower compared to the blends, which contain coarserAPI.

Batch G03 also had the worst flowability of all final blends. This mayalso be explained by the use of micronised API.

Tabletting

Final blends from batches GO1 to G04 and a part of final blend batch G05were compressed as a 100 mg dose strength as free base equivalent. Theother part of the final blend batch G05 was compressed as a 25 mg dosestrength as free base equivalent.

During compression of the 100 mg dose strength as free base equivalentbatches GO1, G02, G04 and G05, no further problems occurred.Surprisingly, it was found that the tablet weight was fluctuating duringcompression of batch G03. Unexpectedly, problems with uniformity ofweight occurred. In addition, the tablet mass was sticking to the tools.It was obvious that both problems were caused by use of the micronisedAPI. Therefore, it is advantageous to omit a micronisation step fortabletting, which will result in better handling and less productiontime.

Compression of the 25 mg dose strength as free base equivalent batch G05was done without problems.

The IPC (in process checks) data of batches GO1-G05 are shown in Tables4 and 5.

TABLE 4 IPC data 100 mg strength as free base equivalent NominalParameter value G01 G02 G03 G04 G05 Weight [mg] 485-515 498 500 497 506516 Diameter 10.8-11.2 12.1 12.1 12.1 12.1 12.1 [mm] Height [mm]determine 5.7-5.8 5.7 5.7-5.8 5.7 5.6-5.7 Hardness [N] >50 73 70 67 7487 Disintegration <5 20-30 sec 15-25 sec 20-30 sec 20-25 sec 15-25 sec[min]

TABLE 5 IPC data 25 mg strength as free base equivalent NominalParameter value G05 Weight [mg] 122-128 127 Diameter [mm] 6.8-7.2 7.1Height [mm] determine 3.6-3.7 Hardness [N] >50 56 Disintegration <5 20-28 sec [min]

Analytics

Tablets or capsules taken orally remain one of the most effective meansof treatment available. The effectiveness of such dosage forms relies onthe drug dissolving in the fluids of the gastrointestinal tract prior toabsorption into the systemic circulation. The rate of dissolution of thetablet or capsule is therefore crucial.

Dissolution: The criteria for dissolution in media with a pH of 1 isQ=75 after 45 minutes.

Influence of particle size distribution on the dissolution: Dissolutionof cores from batches GO1 to G05 was performed. The dissolution resultsare shown in FIG. 8 and Table 6.

TABLE 6 Dissolution results for batches G01-G05 15 30 45 Batch (as freeAverage Min Max Average Min Max Average Min Max base equivalent) [%] [%][%] [%] [%] [%] [%] [%] [%] G01 100 mg 90 83 97 93 85 99 96 90 99 G02100 mg 82 80 84 90 88 91 91 90 94 G03 100 mg 100 98 101 100 97 102 10098 102 G04 100 mg 99 97 100 100 98 102 101 101 102 G05 100 mg 90 87 9399 98 102 103 102 105 G05 25 mg 102 101 104 104 102 105 104 102 105

The dissolution results of batches GO1-G05 are according to thespecification. There is no significant difference in the dissolution ofcores, which contains finer or coarser API.

Content Uniformity (CU): Content uniformity of batches GO1 to G04 wastested. The results are shown in Table 7.

TABLE 7 CU results of batches G01-G04 Assay Standard Acceptance Batchmean (%) deviation value G01 98.2 1.1917 3.2 G02 101.2 1.2599 3.0 G0397.9 3.1110 8.1 G04 103.3 1.3640 5.1

All results comply with Ph.Eur. 2.9.40. Content uniformity of batch G03is inferior compared to the content uniformity of the other batches. Itis obvious that this is related to the problems during compression basedon the micronized API.

CONCLUSIONS

The particle size distribution of the API has an influence on the bulkproperties of the final blend and on the tabletting characteristics.Batch G03, which contains the micronized API, has a worse flowability.Therefore, problems with a uniform weight occurred during compression.In addition, sticking problems were observed, and the CU results of thecores are not as good as the results of the cores with non-micronizedAPI. By use of non-micronized API there was no influence of the particlesize distribution, wherein the particle size distribution is preferablydefined by d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9)from 70 to 400 μm with a specific surface area of the particles lessthan 1.0 m²/g, and more preferably defined by d(0.1) from 10 to 75 μm,d(0.5) from 100 to 175 μm, d(0.9) from 200 to 350 μm with a specificsurface area of the particles less than 0.3 m²/g, on uniformity ofweight and CU obtained. The results do not show a marked influence ofthe particle size distribution on the dissolution of the cores as theyare all within the predefined ranges.

Example 3

Tablet comprising 60 mg of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide as freebase equivalent (corresponding to 76.9 mg of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate according to the invention), wherein atleast 65 v/v % are N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate particles, wherein the particle sizedistribution is preferably defined by d(0.1) from 2 to 100 μm, d(0.5)from 30 to 210 μm and d(0.9) from 70 to 400 μm with a specific surfacearea of the particles less than 1.0 m²/g, and more preferably defined byd(0.1) from 10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to350 μm with a specific surface area of the particles less than 0.3 m²/g;content of active compound about 59% (based on an unvarnished tablet):

crystalline N-[5-(aminosulfonyl)-4-methyl- 76.9 mg1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]acetamide monomethane- sulfonic acid monohydrate Avicel PH 101 118.0 mg lactose, fine40.0 mg Ac-Di-Sol 20.0 mg polyinylpyrrolidone 25 10.0 mg magnesiumstearate 2.0 mg total weight 266.9 mg

Example 4

Tablet comprising 50 mg of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide as freebase equivalent (corresponding to 64 mg of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate), wherein at least 65 v/v % areN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate particles, wherein the particlesize distribution is preferably defined by d(0.1) from 2 to 100 μm,d(0.5) from 30 to 210 μm and d(0.9) from 70 to 400 μm with a specificsurface area of the particles less than 1.0 m²/g, and more preferablydefined by d(0.1) from 10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9)from 200 to 350 μm with a specific surface area of the particles lessthan 0.3 m²/g; content of active compound about 59% (based on anunvarnished tablet):

crystalline N-[5-(aminosulfonyl)-4-methyl- 64.0 mg1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)- phenyl]acetamide monomethane- sulfonic acid monohydrate polyinylpyrrolidone 25 3.5 mgmicrocrystalline cellulose 20.0 mg croscamellose sodium 10.0 mgmagnesium stearate 0.9 mg optionally HPMC varnish 3.0 mg total weight101.4 mg

Example 5

Crystal structure ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidemono methanesulfonic acid monohydrate Formula C₁₉H₂₄N₄O₇S₃, M=516.62,F(000)=540, colorless plate, size 0.02.0.13.0.15 mm³, triclinic, spacegroup P -1 , Z=2, a=9.4908(7)Å, b=9.5545(7) Å, c=14.4137(9) Å,α=86.130(3)°, β=72.104(3)°, γ=68.253(4)°, V =1153.68(15) Å³,D_(calc)=1.487 Mg.m⁻³. The crystal was measured on a Nonius KappaCCDdiffractometer at 293 K using graphite-monochromated Mo K_(α)-radiationwith λ=0.71073 Å, Θ_(max)=30.065°. Minimal/maximal transmission0.95/0.99, μ=0.370 mm⁻¹. The COLLECT suite has been used for datacollection and integration. Of 43492 reflections in total, 6761 wereindependent (merging r=0.026). From these, 4955 were considered observed(I>3.0σ(I)) and were used to refine 298 parameters. The structure wassolved by direct methods using the program SIR92. Least-squaresrefinement against F was carried out on all non-hydrogen atoms using theprogram CRYSTALS. R=0.0313 (observed data), wR=0.0432 (all data),GOF=1.0736. Minimal/maximal residual electron density=−0.28/0.33 e Å⁻³.Chebychev polynomial weights were used to complete the refinement.

Table 8 shows single-crystal structure parameters forN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate.

TABLE 8 Single-crystal structure parameters forN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate Parameter Value formula C₁₉H₂₄N₄O₇S₃formula weight 516.62 g/mol Z, calculated density 2, 1.487 Mg × m⁻³F(000) 540 description and size of crystal Colorless plate, 0.02 × 0.13× 0.15 mm³ absorption coefficient 0.370 mm⁻¹ min/max transmission0.95/0.99 temperature 293K radiation (wavelength) Mo K□□(□ = 0.7103 Å)crystal system, space group Triclinic, P −1 a  9.4908 (7) Å b  9.5545(7)Å c 14.4137(9) Å □ 86.130(3)° □ 72.104(3)° Y 68.253(4)° V 1153.68(15) Å³min/max Θ  2.426°/30.065° number of collected reflections 43492 numberof independent reflections 6761 (merging r = 0.026) number of observedreflections 4955 (l > 3.0□(1)) number of refined parameters 298 r 0.0313(observed data with) rW 0.0432 (all data) goodness of fit 1.0736residual electron density −0.28/0.33 eÅ⁻³

Example 6

Single-dose escalation and pharmacokinetics

An advantage of the tablets according to the invention is that thetablet will have an optimised dissolution rate based on the particlesize distribution of the crystalline form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate, wherein the particle sizedistribution is preferably defined by d(0.1) from 2 to 100 μm, d(0.5)from 30 to 210 μm and d(0.9) from 70 to 400 μm with a specific surfacearea of the particles less than 1.0 m²/g, and more preferably defined byd(0.1) from 10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to350 μm with a specific surface area of the particles less than 0.3 m²/g,and thus, the drug may be absorbed into the blood stream much fastercompared toN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamideas crystalline free base form. Furthermore, the surprising dispersiontimes obtained with tablets according to the invention are advantageousfor swallowable tablets. In a further embodiment, the tablets accordingto the invention can be presented for dispersion in water.

Therefore, pharmacokinetic studies in human subjects were undertakenfollowing both single and multiple dose administrations of thecrystalline mono mesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide,wherein the particle size distribution is preferably defined by d(0.1)from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9) from 70 to 400 μmwith a specific surface area of the particles less than 1.0 m²/g, andmore preferably defined by d(0.1) from 10 to 75 μm, d(0.5) from 100 to175 μm, d(0.9) from 200 to 350 μm with a specific surface area of theparticles less than 0.3 m²/g.

Single oral doses of the crystalline mono mesylate monohydrate salt ofN-[5-(aminosulfonyl)4methyl1,3thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide using theformulations according to example 2, Table 2, were administered to sixvolunteers per dose step. The overall shape of the plasma concentrationsvs. time profiles were similar across all doses (see FIG. 9 and FIG.12).

There was a rapid and continuous increase of plasma concentrations ofthe free base ofN-[5-(aminosulfonyl)4methyl1,3thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide switching into a period of markedly slower absorptionrate and evidence of a plateau effect in exposure. Thereafter, for alldoses investigated, there was a decrease of concentrations of the freebase ofN-[5-(aminosulfonyl)4methyl1,3thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidestarting after 4.0 to 4.5 hours post administration of the crystallinemono mesylate monohydrate salt ofN-[5-(aminosulfonyl)4methyl1,3thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide. This phase was followed by a phase of prolongedexposure, which was characterised by a long half-life, which isfavorable for the treatment of infectious diseases. The mean terminalelimination half-life (t_(1/2z)) ranged between 52 h and 85 h. For dosesfrom 5 mg to 480 mg as free base equivalent there was adose-proportional increase in AUC_(0-∞)(AUC, area under curve); a singledose of 600 mg as free base equivalent did not cause any further rise ofexposure as shown by AUC_(0-∞)(see FIG. 9 and FIG. 12).

Maximum plasma concentrations were linearly related to doses from 5 mgto 400 mg as free base equivalent. At the higher dose up to 600 mg asfree base equivalent no further increase of exposure was obtained asshown by the both C_(max) and AUC_(0-∞). Median t_(max) ranged from 1.5to 4.25 hours without any obvious relation to dose. A summary ofsingle-dose pharmacokinetic parameters is shown in Table 9.

Table 9: Pharmacokinetic parameters after ascending single oral doses ofcrystalline mono mesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide in theformulations according to the formulation described on page 20 whereinthe particle size distribution is preferably defined by d(0.1) from 2 to100 μm, d(0.5) from 30 to 210 μm and d(0.9) from 70 to 400 μm with aspecific surface area of the particles less than 1.0 m²/g, and morepreferably defined by d(0.1) from 10 to 75 μm, d(0.5) from 100 to 175μm, d(0.9) from 200 to 350 μm with a specific surface area of theparticles less than 0.3 m²/g.

In the following the abbreviations used in Table 9 are defined.AUC_(0-∞): Area under the analyte vs. time concentration from time ofadministration up to infinity, calculated as

${AUC}_{0 - \infty} = {{AUC}_{0 - {last}} + \frac{C_{last}}{\lambda_{z}}}$

wherein AUC_(0-∞-last) is defined as the area under the analyte vs. timeconcentration up to time of the last qualifiable concentration,calculated by linear up/log down summation and C_(last) is defined aslast quantifiable observed analyte concentration. λ_(z) is the apparentterminal elimination rate constant, determined by linear regression ofterminal points of In-linear analyte concentration-time curve. C_(max)is the maximal observed analyte concentration and t_(max) is the time toreach C_(max), t_(1/2z) is defined as the apparent terminal eliminationhalf-life, calculated as

${t_{1\text{/}2z} = \frac{\ln (2)}{\lambda_{z}}},$

wherein λ_(z) is defined as above.

MRT: Mean Residence Time; calculated AUMC divided by AUC, wherein AUMCis the area under the first moment of the concentration-time curve fromzero up to ∞ with extrapolation of the terminal phase and AUC is thearea under the concentration-time curve from zero up to ∞ withextrapolation of the terminal phase. CL/F refers to the clearance afteroral administration of a drug and A_(e) refers to the amount of drugexcreted in the urine.

TABLE 9 dose [mg] parameter (means; n = 6 volunteers/dose) free baseAUC_(0-∞) C_(max) t_(max) ^(a) t_(1/2z) MRT CL/F A_(e) equivalent [ng ·h/mL] [ng/mL] [h] [h] [h] [L/h] [% of dose]  5  5800  74 4.00 80 1170.89 0  10 11670  170 1.50 85 116 0.87 0  20 18540  234 2.77 76 105 1.100  40 40680  608 3.50 72 94 1.00 0  80, 87220 1306 2.50 74 94 0.94 0.16males  (99790)^(b)  (1499)^(b)  80, 96230 1999 4.00 58 77 0.85 0.31females  (90050)^(b)  (1853)^(b) 160 130800  2613 3.50 63 83 1.28 0.15240 216900  3600 4.00 64 82 1.15 0.21 320 241100  4648 2.25 57 70 1.470.16 400 320300  6926 4.25 57 64 1.31 0.15 480 387200  6921 3.25 53 721.33 0.26 600 320800  6442 4.25 52 65 2.00 0.09 ^(a)for tmax the medianis given, ^(b)value normalized to body weight for a 70 kg subject;

Based on data for the 80 mg dose as free base equivalent (see also FIG.13), women appeared to exhibit a higher exposure compared to malesaccording to AUC_(0-∞) and C_(max) (see Table 9). However, normalizationto body weight revealed that this apparent difference could be explainedby the lower body weight of the female volunteers compared to males (seeFIG. 13).

Summary of the results of Example 6: For doses from 5 mg to 400 and 480mg as free base equivalent, respectively, there was a linear, i.e.dose-proportional, increase in AUC_(0-∞) and C_(max) with dose; higherdoses do not further increase the exposure. The mean terminalelimination half-life (t_(1/2z)) ranged between 52 h and 85 h (see FIG.12). No clinical relevant gender-related difference in exposure wasdetected for a single dose of 80 mg as free base equivalent (see FIG.13).

Example 7

Multiple-dose escalation and pharmacokinetics For the three doses of themono mesylate monohydrate salt of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide informulation according to example 1, Table 2, wherein the particle sizedistribution is preferably defined by d(0.1) from 2 to 100 μm, d(0.5)from 30 to 210 μm and d(0.9) from 70 to 400 μm with a specific surfacearea of the particles less than 1.0 m²/g, and more preferably defined byd(0.1) from 10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to350 μm with a specific surface area of the particles less than 0.3 m²/g,investigated (5, 25, and 100 mg as free base equivalent; once per dayoral administration, 20 days), the individual concentration-time curvesof the free baseN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]Nmethyl-2-[4-(2-pyridinyl)phenyl]acetamideat day 1 (after the first administration) were very similar in theirgeneral shape and slope to those profiles obtained in the single doseescalation trial (see Example 6). As for the single dose escalationtrial presented in Example 6, there were dose-proportional increases inAUC_(0-24h) and C_(max) at day 1.

During the 20-day treatment with administrations of the mono mesylatemonohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide,wherein the particle size distribution is preferably defined by d(0.1)from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9) from 70 to 400 μmwith a specific surface area of the particles less than 1.0 m²/g, andmore preferably defined by d(0.1) from 10 to 75 μm, d(0.5) from 100 to175 μm, d(0.9) from 200 to 350 μm with a specific surface area of theparticles less than 0.3 m²/g, once daily, the attainment of steady-stateconditions was demonstrated by virtually identical minimal or “trough”concentrations of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamideachieved between days 9 and 13. At steady state, there was a lowinter-individual variability of minimal or “trough” concentrations withCVs (coefficient of variations) between 16.7 and 21.7% (day 21). For alldoses, the individual and mean concentration-time curves of the freebase of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acet-amide at day 21were very similar in their shape and slope to those profiles obtained atday 1.

Table 10 summarizes the steady-state pharmacokinetics of the free baseof N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide.

Table 10: Steady state pharmacokinetic parameters of the free baseN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide at day 21after daily administrations of 5, 25, or 100 mg as free base equivalentof the mono mesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide informulation according to example 2, Table 2, wherein the particle sizedistribution is preferably defined by d(0.1) from 2 to 100 μm, d(0.5)from 30 to 210 μm and d(0.9) from 70 to 400 μm with a specific surfacearea of the particles less than 1.0 m²/g, and more preferably defined byd(0.1) from 10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to350 μm with a specific surface area of the particles less than 0.3 m²/g,to healthy volunteers (n =12 per dose).

In the following the abbreviations used in Table 10 are defined.C_(trough): measured plasma concentration immediately before dosing atday 21 (at the end of the dosing interval at steady state); AUC_(t),i.e. the steady state AUC (area under the curve) within the dosinginterval of 24 hours, C_(max,ss) refers to the maximal observed analyteconcentration at steady state. C_(av) is defined as average plasmaconcentration during the dosing interval the mono mesylate monohydratesalt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamideat steady state, R-AUC refers to the accumulation ratio of the AUC, i.e.AUC_(t)/AUC_(0-24h,dayl), R-C_(max) refers to accumulation ratio ofC_(max), i.e. C_(max,ss)/C_(max,day1); t_(1/2z) is defined as above

TABLE 10 dose [mg] as free AUC_(T) base C_(trough) [ng · C_(max, ss)C_(av) t_(1/2z) equivalent [ng/mL] h/mL] [ng/mL] [ng/mL] R-AUC R-C_(max)[h] 5 187 5094 301 213 5.2 5.0 82.6 25 832 23430 1358 977 5.3 5.3 68.6100 3743 108800 6358 4540 5.1 5.3 59.8

For the three doses applied, there was a dose-proportional increase forall measures of exposure at steady state (C_(trough), AUC_(t),C_(max,ss), and C_(av)) (see Table 10). For both AUC and C_(max), theaccumulation ratio R of all doses applied was very similar beingapproximately a factor of 5 (see Table 10). The time to reach C_(max,ss)was similar for the three doses (0.5-4.5 h). The peak-trough fluctuationat steady-state ranged between 59 and 64%. Elimination half-life was inthe same range as after single-dose application with 82.6 h (5 mg), 68.6h (25 mg), and 59.8 h (100 mg). The apparent total clearance (CL/F) wasestimated to be similar for all doses investigated (0.99-1.08 L/h).

Summary of the results of Example 7: Under steady-state conditions, anincrease in the dose of mono mesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide informulation according to example 2, Table 2, wherein the particle sizedistribution is preferably defined by d(0.1) from 2 to 100 μm, d(0.5)from 30 to 210 μm and d(0.9) from 70 to 400 μm with a specific surfacearea of the particles less than 1.0 m²/g, and more preferably defined byd(0.1) from 10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to350 μm with a specific surface area of the particles less than 0.3 m²/g,resulted in a proportional increase in exposure to the resultant freebase ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide.In general, plasma concentrations at steady state are to be expected tobe approximately five times higher than after single dose administrationof the same dose. This should be a reflection of the half-life anddosing interval. Inter-individual variability of steady state exposurewas quite low as revealed by a low coefficient of variation, e.g. forminimal or “trough” concentrations and peak-trough fluctuations. Rate ofelimination and terminal half-lives at steady-state were comparable tothe single dose situation.

Example 8

Pharmacokinetic/pharmacodynamic correlation

To assess the pharmacokinetic/pharmacodynamic profile the effective doseof the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamidewas validated in a murine HSV skin infection model and associated plasmaconcentrations were determined (data not shown).

The results were compared with the effective concentration of the freebase of N-[5-(aminosulfonyl)-4-methyl-1, 3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide in cellculture and correlated to exposures reached in healthy male volunteersin single and multiple dose phase I trials (see FIGS. 9-13).

Oral doses of 5 mg/kg of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide or higheronce daily doses for four days completely suppressed the murineinfection (data not shown). Associated plasma concentrations in micedetermined with a single oral dose of 10 mg/kg of the free base formwere well above the cell culture EC₉₀ adjusted for protein binding overthe entire dosing interval of 24 h. In healthy male volunteers theseplasma concentrations were covered by a single dose of 40 mg as freebase equivalent to the crystalline mono mesylate monohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide(see FIG. 10) and at steady state by daily doses of 25 mg as free baseequivalent (see FIG. 11) for 21 days. In both settings the resultantfree base of N-[5-(aminosulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]-acetamide was safe andwell tolerated up to the highest dose tested.

In summary, the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamideexhibits advantageous PK/PD profiles in non-clinical studies andexposures required to suppress HSV replication were reached in humans.

Specifically, the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide,resultant from the herein described crystalline mono mesylatemonohydrate salt ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2[4-(2-pyridinyl)phenyl]acetamidewherein the particle size distribution is preferably defined by d(0.1)from 2 to 100 μm, d(0.5) from 30 to 210 μm and d(0.9) from 70 to 400 μmwith a specific surface area of the particles less than 1.0 m²/g, andmore preferably defined by d(0.1) from 10 to 75 μm, d(0.5) from 100 to175 μm, d(0.9) from 200 to 350 μm with a specific surface area of theparticles less than 0.3 m²/g, exhibits advantageous PK/PD profiles innon-clinical studies and exposures required to suppress HSV replicationwere reached in humans.

These results clearly demonstrate that using the mono mesylatemonohydrate salt of N-[5-(aminosulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide, wherein theparticle size distribution is preferably defined by d(0.1) from 2 to 100μm, d(0.5) from 30 to 210 μm and d(0.9) from 70 to 400 μm with aspecific surface area of the particles less than 1.0 m²/g, and morepreferably defined by d(0.1) from 10 to 75 μm, d(0.5) from 100 to 175μm, d(0.9) from 200 to 350 μm with a specific surface area of theparticles less than 0.3 m²/g in the formulations as described above, aonce daily dose (or even a less frequent administration) is sufficientfor reaching an appropriate plasma concentration for the treatment ofviral diseases, e.g. infection by a herpes virus or herpes viruses. In afurther human trial it has been shown that the administration of ahigher dose of 400 mg to 600 mg as free base equivalent and preferablyabout 500 mg as free base equivalent of the crystalline mono mesylatemonohydrate salt of the present invention is also sufficient forreaching an appropriate plasma concentration for the treatment of viraldiseases, e.g. infection by a herpes virus or herpes viruses.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 Shows the overlay of X-ray powder diffractions obtained aftergranulation experiments; from top to bottom:

N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidemono mesylate monohydrate (200441092)

free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide(200472682),

N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide,granulation of free base using 1 equivalent of methanesulfonic acidaccording to WO 2006/103011, example 5 (200472053);

lowest curve shows blank granulation matrix (200472054). A 1:1 (weightper weight) mixture of the free base and the mono mesylate monohydratewas analyzed with X-ray powder diffraction as calibration of the ratioof free base to salt. The ratio was calculated based on integration andshows the granulation mixture having a content of the mono mesylatemonohydrate form of 8 to 12 percent.

FIG. 2 Shows the overlay of X-ray powder diffraction spectra ofgranulations of a mixture of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidemono methanesulfonic acid monohydrate withN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidemono methanesulfonic acid after closed storage at 40° C. for four weeks(top; 200478116), after closed storage at 40° C. for four days (middle;200474092) and of the initial sample, i.e. the mixture ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidemono methanesulfonic acid monohydrate withN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidemono methanesulfonic acid (200472053).

FIG. 3A Shows microscope pictures of the free base form ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide.

FIG. 3B Shows microscope pictures of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate.

FIG. 3C Shows microscope pictures of spontaneous crystallized materialafter addition of methanesulfonic acid.

FIG. 4 Shows the X-ray structure of the crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate with indicated hydrogen bridges. It isshown that the nitrogen atom in the pyridinyl ring (right side bottom)is protonated and that a hydrogen bridge is formed between the hydrogen,which protonates the pyridinyl ring nitrogen and one oxygen of themesylate anion, and another hydrogen bridge is formed between anotheroxygen of the mesylate anion and the hydrogen of the water moleculewhile the other hydrogen of the water molecule form a hydrogen bridgewith the oxygen of another mesylate anion.

FIG. 5 Shows the X-ray powder diffraction spectra of a film-coatedtablet with 5 mg as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate, wherein the particle size distributionis preferably defined by d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210μm and d(0.9) from 70 to 400 μm with a specific surface area of theparticles less than 1.0 m²/g, and more preferably defined by d(0.1) from10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to 350 μm with aspecific surface area of the particles less than 0.3 m²/g (Nr. 1), aplacebo tablet (Nr. 2) and ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide mono methanesulfonic acid monohydrate (Nr. 3) after 24months at 25° C.

FIG. 6 Shows the X-ray powder diffraction spectra of a film-coatedtablet with 25 mg as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate, wherein the particle size distributionis preferably defined by d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210μm and d(0.9) from 70 to 400 μm with a specific surface area of theparticles less than 1.0 m2/g, and more preferably defined by d(0.1) from10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to 350 μm with aspecific surface area of the particles less than 0.3 m²/g (Nr. 1), aplacebo tablet (Nr. 2) and ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidemono methanesulfonic acid monohydrate (Nr. 3) after 24 months at 25° C.

FIG. 7 Shows the X-ray powder diffraction spectra of a film-coatedtablet with 100 mg as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate, wherein the particle size distributionis preferably defined by d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210μm and d(0.9) from 70 to 400 μm with a specific surface area of theparticles less than 1.0 m²/g, and more preferably defined by d(0.1) from10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to 350 μm with aspecific surface area of the particles less than 0.3 m²/g (Nr. 1), aplacebo tablet (Nr. 2) and ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidemono methanesulfonic acid monohydrate (Nr. 3) after 24 months at 25° C.

FIG. 8 Shows the dissolution curves of the six different tabletsaccording to Table 7 (G01-G05 indicated by marked lines and arrows).

FIG. 9 Shows the relationship between single doses [mg] (5 mg-600 mg asfree base equivalent) of tablets containing crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate, wherein the particle size distributionis preferably defined by d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210μm and d(0.9) from 70 to 400 μm with a specific surface area of theparticles less than 1.0 m²/g, and more preferably defined by d(0.1) from10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to 350 μm with aspecific surface area of the particles less than 0.3 m²/g, and AUCinf[ng*h/mL] (identical to AUC_(0-∞)), measured as the free base ofN-[5-(aminosulfonyl) -4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide.

FIG. 10 Shows plasma time curves of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide measured byHPLC in plasma of healthy male volunteers (n=6) after a single oral doseof tablets containing 5 mg; 10 mg; 20 mg and 40 mg as free baseequivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamidemono methanesulfonic acid monohydrate, wherein the particle sizedistribution is preferably defined by d(0.1) from 2 to 100 μm, d(0.5)from 30 to 210 μm and d(0.9) from 70 to 400 μm with a specific surfacearea of the particles less than 1.0 m²/g, and more preferably defined byd(0.1) from 10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to350 μm with a specific surface area of the particles less than 0.3 m²/g.The four different doses were administered as immediate release tabletsand blood was collected at indicated time points after administration.The free base concentration was measured by HPLC in plasma. The EC₉₀derived from cell culture was corrected for protein binding taking intoaccount the fraction unbound of N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2- [4-(2-yridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate in cell culture medium (71%) and inmurine plasma (2.8%). Plasma concentrations remained over the EC₉₀ forthe entire treatment interval after administration of 40 mg as free baseequivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-yridinyl)phenyl]acetamidemono methanesulfonic acid monohydrate once daily at steady state. EC₉₀denotes 90% effective concentration.

FIG. 11 Shows plasma time curve of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl] acetamide afteradministration of tablets containing 5 mg and 25 mg as free baseequivalent of crystalline N-[5-(aminosulfonyl)-4-methyl- 1,3-thiazol-2-yl]-N-methyl-2-[4-(2-yridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate, wherein the particle size distributionis preferably defined by d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210μm and d(0.9) from 70 to 400 μm with a specific surface area of theparticles less than 1.0 m²/g, and more preferably defined by d(0.1) from10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to 350 μm with aspecific surface area of the particles less than 0.3 m²/g in fasted,male healthy volunteers (n=12) after multiple dose administrationthereof once daily at day 21 (steady state). The two different doseswere administered as immediate release tablets and blood was collectedat indicated time points after administration. The free baseconcentration was measured by HPLC in plasma. The EC₉₀ derived from cellculture was corrected for protein binding taking into account thefraction unbound ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-yridinyl)phenyl]acetamidemono methanesulfonic acid monohydrate in cell culture medium (71%) andin murine plasma (2.8%). Plasma concentrations remained over the EC₉₀for the entire treatment interval after administration of 25 mg as freebase equivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-yridinyl)phenyl] acetamide monomethanesulfonic acid monohydrate once daily at steady state. EC₉₀denotes 90% effective concentration.

FIG. 12 Shows dose proportionality after single dose administration tofasted male healthy volunteers (n=6) of up to 400/480 mg as free baseequivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-yridinyl)phenyl]acetamidemono methanesulfonic acid monohydrate, wherein the particle sizedistribution is preferably defined by d(0.1) from 2 to 100 μm, d(0.5)from 30 to 210 μm and d(0.9) from 70 to 400 μm with a specific surfacearea of the particles less than 1.0 m²/g, and more preferably defined byd(0.1) from 10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200 to350 μm with a specific surface area of the particles less than 0.3 m²/g.Terminal half-life (t_(1/2z)) is between 52 h and 85 h.

FIG. 13 Shows that the total exposure of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-yridinyl)phenyl]acetamide, resultantfrom crystalline mono methanesulfonic acid monohydrate administrationwith 80 mg single dose as free base equivalent, wherein the particlesize distribution is preferably defined by d(0.1) from 2 to 100 μm,d(0.5) from 30 to 210 μm and d(0.9) from 70 to 400 μm with a specificsurface area of the particles less than 1.0 m²/g, and more preferablydefined by d(0.1) from 10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9)from 200 to 350 μm with a specific surface area of the particles lessthan 0.3 m²/g to woman is higher (triangle) compared to males (dots) forn=6. After normalization to body weight no relevant gender differencescould be revealed.

1-27. (canceled)
 28. A composition of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate particles of the following formula

having a purity of >99%, wherein said particles in the composition havea particle size range from 1 to 500 μm, a particle size distributionwhich is defined by d(0.1) from 2 to 100 μm, d(0.5) from 30 to 210 μmand d(0.9) from 70 to 400 μm and a specific surface area of less than1.0 m²/g.
 29. The composition of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate particles according to claim 28,wherein the N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate particles have a particle size rangefrom 2 μm to 400 μm.
 30. The composition of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate particles according to claim 28,wherein the particles have a particle size distribution which is definedby d(0.1) from 10 to 75 μm, d(0.5) from 100 to 175 μm, d(0.9) from 200to 350 μm.
 31. The composition of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate particles according to claim 28,wherein the particles have a specific surface area of less than 0.3m²/g.
 32. A combination of the composition of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl] acetamide monomethanesulfonic acid monohydrate particles according to claim 28 andacetylsalicylic acid, trifluridine, idoxuridine, foscarnet, cidofovir,ganciclovir, aciclovir, penciclovir, valaciclovir, famciclovir and/orvalganciclovir.
 33. A pharmaceutical composition comprising thecomposition of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)phenyl]acetamide monomethanesulfonic acid monohydrate particles as defined in claim 28 and atleast one pharmaceutically acceptable carrier, excipient, solvent and/ordiluent.
 34. The pharmaceutical composition according to claim 33,wherein the composition of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate particles have a particle sizerange from 2μm to 400 μm.
 35. The pharmaceutical composition accordingto claim 33, wherein the composition of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate particles have a particle sizedistribution which is defined by d(0.1) from 10 to 75 μm, d(0.5) from100 to 175 μm, d(0.9) from 200 to 350 μm.
 36. The pharmaceuticalcomposition according to claim 33, wherein the composition ofcrystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate particles have a specific surfacearea of less than 0.3 m²/g.
 37. A combination of the pharmaceuticalcomposition according to claim 33 and acetylsalicylic acid,trifluridine, idoxuridine, foscarnet, cidofovir, ganciclovir, aciclovir,penciclovir, valaciclovir, famciclovir and/or valganciclovir.
 38. Thepharmaceutical composition according to claim 33, which is effective toachieve an absolute bioavailability of 70%±30% of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide, whenadministered in said composition containing at least 25 mg as free baseequivalent of the crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate.
 39. The pharmaceutical compositionaccording to claim 33, which is effective to achieve a mean maximumblood plasma concentration (mean C_(max)) of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide in a subjectof at least one of a) 608±184 ng/ml for a 40 mg dosage as free baseequivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate, said dosage being a single oraldose administered; b) 1306±125 ng/ml for a 80 mg dosage as free baseequivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate, said dosage being a single oraldose administered; c) 2613±1341 ng/ml for a 160 mg dosage as free baseequivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl] acetamide mono methanesulfonic acid monohydrate, said dosagebeing a single oral dose administered; d) 3600±752 ng/ml for a 240 mgdosage as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1, 3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, said dosage being a single oral doseadministered; e) 4648±1813 ng/ml for a 320 mg dosage as free baseequivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, said dosage being a single oral doseadministered; f) 6926±1656 ng/ml for a 400 mg dosage as free baseequivalent of crystalline N- [5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, said dosage being a single oral doseadministered; g) 6921±2190 ng/ml for a 480 mg dosage as free baseequivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate, said dosage being a single oraldose administered.
 40. The pharmaceutical composition according to claim33, which is effective to achieve a mean maximum blood plasmaconcentration (mean C_(max)) of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidein a subject of at least one of a) 608±184 ng/ml for a 40 mg dosage asfree base equivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl] acetamide monomethanesulfonic acid monohydrate and/or effective to achieve anAUC_(0-24h) of 10090±3114 ng-h/ml in a subject for a 40 mg dosage asfree base equivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, and wherein t_(1/2z) is 72±3 h onaverage; said dosage being a single oral dose administered; b) 1306±125ng/ml for a 80 mg dosage as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate and/or effective to achieve anAUC_(0-24h) of 21940±2057 ng-h/ml in a subject for a 80 mg dosage asfree base equivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, and wherein t_(1/2z) is 74±5 h onaverage; said dosage being a single oral dose administered; c) 2613±1341ng/ml for a 160 mg dosage as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate and/or effective to a achieve anAUC_(0-24h) of 40470±16700 ng-h/ml in a subject for a 160 mg dosage asfree base equivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, and wherein t_(1/2z) is 63±6 h onaverage; said dosage being a single oral dose administered; d) 3600±752ng/ml for a 240 mg dosage as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate and/or effective to achieve anAUC_(0-24h) of 59610±12770 ng-h/ml in a subject for a 240 mg dosage asfree base equivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, and wherein t_(1/2z) is 64±5 h onaverage; said dosage being a single oral dose administered; e) 4648±1813ng/ml for a 320 mg dosage as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate and/or effective to achieve anAUC_(0-24h) of 76250±27630 ng-h/ml in a subject for a 320 mg dosage asfree base equivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, and wherein t_(1/2z) is 57±3 h onaverage; said dosage being a single oral dose administered; f) 6926±1656ng/ml for a 400 mg dosage as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate and/or effective to achieve anAUC_(0-24h) of 104800±25740 ng-h/ml in a subject for a 400 mg dosage asfree base equivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, and wherein t_(1/2z) is 57±4 h onaverage; said dosage being a single oral dose administered; g) 6921±2190ng/ml for a 480 mg dosage as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate and/or effective to achieve anAUC_(0-24h) of 112800±34260 ng-h/ml in a subject for a 480 mg dosage asfree base equivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, and wherein t_(1/2z) is 53±4 h onaverage; said dosage being a single oral dose administered.
 41. Thepharmaceutical composition according to claim 33, which is effective toachieve a mean maximum blood plasma concentration at steady state (meanC_(max,ss)) of the free base ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidein a subject of at least one of a) 1358±167 ng/ml for a 25 mg dosage asfree base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate, said dosage being a steady statedose achieved after once daily single doses administered for 21 days; b)6358±1701 ng/ml for a 100 mg dosage as free base equivalent ofcrystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate, said dosage being a steady statedose achieved after once daily single doses administered for 21 days; c)9987±2608 ng/ml for a 200 mg dosage as free base equivalent ofcrystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide mono methanesulfonic acid monohydrate,said dosage being a steady state dose achieved after once daily singledoses administered for 21 days.
 42. The pharmaceutical compositionaccording to claim 33, which is effective to achieve a mean maximumblood plasma concentration at steady state (mean C_(max,ss)) of the freebase ofN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidein a subject of at least one of a) 1358±167 ng/ml for a 25mg dosage asfree base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide mono methanesulfonic acid monohydrate and/or effective toachieve an AUC_(t,ss) of 23430±3020 ng-h/ml in a subject for a 25 mgdosage as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, and wherein t_(1/2z) is 69±6 h onaverage, said dosage being a steady state dose achieved after once dailysingle doses administered for 21 days; b) 6358±1701 ng/ml for a 100 mgdosage as free base equivalent of crystallineN-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamidemono methanesulfonic acid monohydrate and/or effective to achieve anAUC_(t,ss) of 108800±28610 ng-h/ml in a subject for a 100 mg dosage asfree base equivalent of crystalline N-[5-(aminosulfonyl)-4-methyl-1,3-thiazol-2-yl]-N-methyl-2-[4-(2-pyridinyl)-phenyl]acetamide monomethanesulfonic acid monohydrate, and wherein t_(1/2z) is 60±4 h onaverage, said dosage being a steady state dose achieved after once dailysingle doses administered for 21 days.
 43. The pharmaceuticalcomposition of claim 38, wherein said absolute bioavailability isachieved in a human.
 44. The pharmaceutical composition of claim 39,wherein said mean C_(max) is achieved in a human.
 45. The pharmaceuticalcomposition of claim 40, wherein said AUC_(0-24h) and t_(1/2z) areachieved in a human.
 46. The pharmaceutical composition of claim 42,wherein said AUC_(t,ss) and t_(1/2z) are achieved in a human.
 47. Thepharmaceutical composition of claim 40, wherein said mean C_(max) isachieved in a human.
 48. The pharmaceutical composition of claim 41,wherein said mean C_(max,ss) is achieved in a human.
 49. Thepharmaceutical composition of claim 42, wherein said mean C_(max,ss) isachieved in a human.